Optic Neuritis: A Review PN Shams , GT Plant

Optic Neuritis: A Review
●
Optic Neuritis: A Review
PN Shams1,2, GT Plant1,2,3
1The
National Hospital for Neurology & Neurosurgery, London, UK; 2Moorfields Eye Hospital, London, UK;
3St Thomas’ Hospital, London, UK
Summary
Acute demyelinating optic neuritis (ON) is the initial
impact on long-term visual outcome. In the ONTT
presentation in approximately 20% of cases of multiple
the 10-year risk of recurrence of demyelinating ON was
sclerosis (MS) and is characterized by unilateral, subacute,
35%. The presence of white matter lesions on the initial
painful visual loss without systemic or neurological
magnetic resonance image of the brain has been identified
symptoms. The Optic Neuritis Treatment Trial (ONTT) has
as the strongest predictor for the development of MS. The
provided valuable insights into both the natural history
15-year risk of developing MS in the ONTT was 25% with
and clinical course of demyelinating ON with respect to
no lesions, but 75% with one or more lesions. Since there
treatment. Visual function improves spontaneously over
is evidence of early axonal damage in acute demyelinating
weeks and within 12 months 93% have recovered to a
ON, disease-modifying drugs should be considered in
visual acuity of at least 20/40. Treatment with high-dose
patients at high risk of developing MS in the future as
corticosteroids may accelerate visual recovery, but has little
prophylaxis against permanent neurological impairment.
KEY WORDS:
OPTIC
NEURITIS;
MULTIPLE
DISEASE-MODIFYING
SCLEROSIS;
OPTIC
NEURITIS TREATMENT TRIAL;
DEMYELINATING
OPTIC NEUROPATHY;
CORTICOSTEROIDS;
DRUGS
Introduction
In most parts of the world acute demyelinating optic
neuritis (ON) is the most common cause of unilateral
painful visual loss in a young adult. In those regions
where multiple sclerosis (MS) is common, most cases
of ON are related to that disorder, although the
diagnosis is not made until a second symptomatic
episode (relapse) when the disorder can be referred
to as MS-associated ON (MSAON). Typical cases
can be referred to as demyelinating ON until a
diagnosis of MS is made. Since ON can herald a
more diffuse demyelinating disease, care should be
taken in making an accurate diagnosis, and careful
consideration given to treatment options, particularly
as other causes of ON not related to MS require
quite different management. The diagnosis of
demyelinating ON is usually made clinically,
although imaging of the optic nerves, preferably by
magnetic resonance imaging (MRI), is mandatory for
atypical cases. MRI of the brain can also yield
82
prognostic information in terms of the patient's
future risk of a second, MS-defining, episode.
Much information has been gleaned from the ON
Treatment Trial (ONTT)1 where 377 patients with
acute ON were prospectively assessed with respect
to visual function, recurrence of optic neuritis and
development of MS over 15 years.2 The design of
the ONTT was to measure visual field and contrast
sensitivity as the primary endpoints of the trial and
visual acuity and colour vision identified as
secondary endpoints.3 This article reviews adult
demyelinating ON as a primary demyelinating
inflammation of the nerve occurring either in isolation
or in association with MS. ON in childhood, bilateral
ON (both excluded from the ONTT) and non-MSassociated ON are important conditions that involve
a different set of clinical phenotypes. We refer the
reader to recent reviews on the differential diagnosis
of ON.4–6
The International MS Journal 2009; 16: 82–89
●
Pathophysiology
The clinical course of demyelinating ON initially
involves an episode of demyelination followed, in
the majority of cases, by near-full recovery; recurrent
attacks are also compatible with good visual
function.7 However a small group of patients will
have a poor visual outcome after a single attack and
progressive visual loss is seen in MS. The
pathogenesis of demyelinating ON is thought to
involve an inflammatory process that leads to
activation of peripheral T-lymphocytes which cross
the blood–brain barrier and cause a delayed type
hypersensitivity reaction culminating in axonal loss.
Clinical recovery reflects the combined effects of
demyelination with conduction block and axonal
injury on the one hand, remyelination with
compensatory neuronal recruitment on the other.
However, irreversible axonal damage occurs
early in the disease process. A study using ocular
coherence tomography (OCT) demonstrated that
axonal injury is common in ON8 and observed
retinal nerve fibre layer (RNFL) thinning in 74% of
individuals within 3 months of acute ON. In this and
another cross-sectional study of MS patients with
ON,9 RNFL was significantly reduced in the affected
eye when compared with fellow eyes or disease-free
controls. These and other studies10 have correlated
RNFL thinning with impaired visual function. OCT
can be employed to monitor such progressive axonal
loss in both primary and secondary progressive MS.11
Epidemiology
For reasons that are not well understood, the
incidence of MSAON is highest in populations
located at higher latitudes, in northern USA, northern
Europe and Australasia and falls significantly closer
to the equator.12 In the USA, studies have estimated
the annual incidence of ON is five per 100 000,
with a prevalence of 115 per 100 000;13 these
demographics closely follow those of MS. In
addition, it is seen more commonly in Caucasians,
and quite rarely in black populations.14 Whites of
northern European descent develop ON eight times
more frequently than blacks and Asians. Studies have
shown that individuals who migrate before puberty
take on the incidence of MS in the area to which
they migrate.15,16 Therefore, an interaction exists
between ethnic origin and the latitude at which the
person grows up.
The International MS Journal 2009; 16: 82–89
Optic Neuritis: A Review
Key Points
• Acute demyelinating ON is the most common cause
of unilateral painful visual loss in a young adult
• The diagnosis of ON is made clinically and
consists of a classic triad of visual loss, periocular
pain and dyschromatopsia
• Recovery of visual loss occurs spontaneously starting
within 2–3 weeks and stabilizing over months
• MRI of the brain can yield prognostic information
in terms of the patient's future risk of a second
MS-defining episode
• The decision to treat with disease-modifying
therapies (DMDs) should be individualized and the
patient fully involved in the decision making process
Clinical Features and Diagnosis
Typically, patients with first presentation of acute
demyelinating ON are otherwise healthy young
adults. A history of preceding viral illness may be
present. There is a female preponderance by a ratio
of approximately 3:1,17 with most patients presenting
between 20 and 45 years of age. Demyelinating ON
is rare in children and is then often related to a postTable 1: Features of typical demyelinating ON
in adults
• Acute to subacute onset – progressive over a few
days to 2 weeks
• Young adult patient, typically less than 45 years
of age, but may be of any age
• Periocular pain (90%), especially with eye
movement – preceding or coinciding with visual loss
• Unilateral loss of visual acuity – variable severity
• Reduced contrast and colour vision – out of
proportion to loss of visual acuity
• Exacerbation of symptoms with increased body
temperature (Uhthoff’s phenomenon)
• Ipsilateral relative afferent pupillary defect
• Normal (65%) or swollen (35%) optic nerve head
• Mild periphlebitis (venous sheathing)
• Visual field defect – almost any type
• Spontaneous visual improvement in >90% starting
within 2–3 weeks regardless of treatment
• No deterioration in vision when corticosteroids are
withdrawn
• Pallor of the optic disc is seen within 4–6 weeks
from onset of visual loss
• Overall, 50% of clinically isolated cases of ON go
on to develop a second MS-defining episode by
15 years. The risk of developing MS is 25% when
baseline MRI is normal and 75% when MRI has one
or more brain lesions typical for MS49,52
• Ancillary investigations suggestive of MS
83
Optic Neuritis: A Review
●
or para-infectious demyelination. In contrast to adults,
demyelinating ON in children presents with bilateral
involvement, in 60–70% of cases, and profound
visual loss at presentation is more common.18–21
The classic triad of inflammatory ON consists of
loss of vision, periocular pain and dyschromatopsia,
and is unilateral in 70% of adults. The typical clinical
course, outlined in Table 1, is that of retro-orbital
pain usually exacerbated by eye movement, and loss
of central vision. Visual loss varies from mild
reduction to no perception of light and progresses
over 7–10 days before reaching a nadir.
Periocular pain occurs in more than 90% of cases,
may precede or coincide with the visual symptoms
and usually resolves over days. All patients show
reduced contrast sensitivity and dyschromatopsia,
which are often out of proportion to the visual acuity
deficit. Most persons show mixed red-green and blueyellow colour defects, one type or the other
predominating.22 Any type of visual field defect is
possible although the ONTT suggested that altitudinal
field defects, arcuate defects and nasal steps were
more common.
The amplitude of the pupillary light reflex is
decreased in the affected eye which is clinically
detected as a relative afferent pupillary defect
(RAPD), an objective, but non-specific sign of optic
neuropathy. In bilateral cases, or in cases with a preexisting optic neuropathy in the fellow eye, an RAPD
may not be apparent. Two-thirds of cases of acute
demyelinating ON are retrobulbar and the optic
nerve appears normal. The disc swelling of
demyelinating ON is diffuse and the presence of
segmental changes, altitudinal swelling, pallor,
arterial attenuation, and splinter haemorrhages should
bring its diagnosis into question.
Additional associated clinical findings include:
a reduction in vision in bright light; Uhthoff’s
phenomenon, exercise- or heat-induced exacerbation
of visual symptoms described in 50% of patients with
isolated ON;23 and the Pulfrich phenomenon, in
which anomalous perception of the direction of
movement of an object occurs due to asymmetry
of conduction velocity in the optic nerves.
Table 2: Differential diagnosis of ON
Corticosteroid-responsive optic neuropathies
Sarcoidosis, systemic lupus erythematosus, Behçet
syndrome, autoimmune ON, NMO, chronic
relapsing inflammatory optic neuropathy
Other inflammatory conditions
Post-infection, post-vaccination, neuroretinitis, acute
disseminated encephalomyelitis
Compressive optic neuropathies
Primary tumours, gliomas, meningioma, pituitary
tumours – particularly craniopharyngioma in
children, metastases, sinus mucocoeles, arterial
aneurysms
Ischaemic optic neuropathies
Anterior and posterior ischaemic optic neuropathy,
giant cell arteritis, diabetic papillopathy
Infective conditions
Tuberculosis, syphilis, Lyme disease, viral ON,
toxocariasis or helminthitis (usually visible
retinal/optic head lesion)
Toxic and nutritional optic neuropathy
Vitamin B12 deficiency, tobacco-ethanol amblyopia,
methanol intoxication, ethambutol toxicity
Inherited conditions
Leber hereditary optic neuropathy
Ocular causes
Posterior scleritis, maculopathy, retinopathy, big
blind spot syndrome
Periorbital infection
Cellulitis, severe suppurative sinusitis
Factitious visual loss
Intentional or ‘hysterical’
publication for a more detailed discussion of the
differential diagnoses of ON.26
Neuromyelitis optica (NMO), also known as
Devic’s disease, is a rare cause of ON associated
with myelitis. When recurrent, this disease has in the
past often been misclassified as MS, but it is a
separate entity that is distinguished from MS by its
severity, by disease location (it affects the optic
nerves and extensive segments of the spinal cord,
largely sparing the brain) and by cerebrospinal fluid
(CSF) analysis (polymorphonuclear pleocytosis and
absence of oligoclonal banding). Serum NMOimmunoglobulin G is a specific autoantibody marker
for NMO, targeting the water channel aquaporin-4
and is found in 70% of cases, suggesting that NMO
may be a novel autoimmune channelopathy.
Investigations
Differential Diagnosis
Misdiagnosis of ON is not uncommon.24,25 Although
demyelination is its most common identifiable cause,
many other causes of optic neuropathy may resemble
ON (see Table 2). The reader is referred to a recent
84
Investigations should be guided by the clinical
presentation. A thorough list of differential diagnoses
including their clinical features and further
management strategy can be found in other reviews
on this topic.4,5,27,28
The International MS Journal 2009; 16: 82–89
●
Table 3: Features of atypical ON in adults
• Age <50 or >12 years
• Bilateral simultaneous or rapidly sequential ON and
chiasmitis
• Severe visual loss – no light perception
• Progressive visual loss for >2 weeks from onset
• Painless visual loss
• Pain following onset of visual loss or persistent pain
for >2 weeks from onset
• Severe pain that restricts eye movements or wakes
patient from sleep
• Unusual ocular findings:
o Marked anterior and/or posterior segment
inflammation
o Marked periphlebitis (venous sheathing)
o Markedly swollen optic nerve head
o Marked optic disc haemorrhages
o Macular star
• Lack of any visual recovery within 5 weeks or
continued deterioration in visual function
• Symptoms or signs of a systemic disorder other
than MS
• African or Asian race
• Family history
• Corticosteroid-dependent optic neuropathy/
deterioration in vision when corticosteroids
are withdrawn
• Previous history of neoplasia
• Ancillary investigations suggestive of a diagnosis
other than MS (NMO, sarcoidosis, Behçet syndrome)
The diagnosis of ON is usually made on clinical
grounds. Neuro-ophthalmic assessments can improve
diagnostic accuracy, and early review is essential to
ensure visual recovery has begun and the diagnosis
reconsidered if it has not. In a typical case of
demyelinating ON as outlined in Table 1, without
any clinical signs and symptoms of a systemic
disease, the yield from diagnostic tests is extremely
low and is of no value in typical cases.29 However, if
there are atypical features, as outlined in Table 3,
suggestive of an alternative diagnosis, a
comprehensive assessment should be undertaken.
The real value of MRI in typical demyelinating ON
is not to image the optic nerves, but to image the
brain as a prognostic indicator for the future
development of MS. Orbital MRI should be reserved
for those suspected of visual loss secondary to
disease processes other than demyelinating ON.
Visual evoked potentials (VEPs) are not helpful in
differentiating between different causes of optic
neuropathy in the acute phase. Subclinical cases may
be confirmed electrophysiologically by VEPs if
dyschromatopsia and optic disc pallor are discovered.
Cerebrospinal fluid analysis is usually not necessary
The International MS Journal 2009; 16: 82–89
Optic Neuritis: A Review
in patients with typical demyelinating ON.30 In the
ONTT only the presence of oligoclonal bands
correlated with later development of MS; even so,
these patients also had an abnormal baseline MRI
which predicted their higher risk of MS, rendering
CSF analysis unnecessary.31 In general, CSF analysis
should be reserved for patients with atypical ON,
especially in children, bilateral cases or when
systemic or infectious diseases are suspected.
Low-contrast letter acuity (Sloan charts) and
contrast sensitivity (Pelli–Robson chart) have been
found to show a high correlation with structural
biomarkers, such as brain MRI32 and RNFL
thickness,9 as measured by OCT, linking visual
function with structural derangements within the
anterior visual system. These simple and reproducible
bedside examinations have been able to
distinguished MS patients from disease-free control
subjects33,34 and are a sensitive clinical measure of
visual dysfunction in both established MS and
subclinical disease.
Visual Prognosis
Recovery of visual loss occurs spontaneously starting
within 2–3 weeks in 80%,7 stabilizing over months
and continuing to improve for up to 1 year.35 In the
ONTT 79% and 93% of patients started to show signs
of improvement within 3 and 5 weeks of onset
respectively.35 In the same study, 1 year following the
initial attack of ON, 93% and 69% had a visual
acuity better than 20/40 and 20/20 in the affected
eye respectively.36 At 15-year follow-up 72%2 (>92%)
of patients had a visual acuity of 20/20 (>20/40) or
better in the affected eye respectively and only 1%
were worse than 20/200 in both eyes.2,7 On
average, visual function was worse in patients
eventually diagnosed with MS than in those without
MS. The severity of initial visual loss does appear to
affect final visual outcome37 and in the ONTT the best
predictor of visual recovery was the baseline acuity at
enrolment.24 A recent analysis of the ONTT database
evaluated predictors of abnormal 6-month vision, and
reported that recovery is not as good with poor
baseline visual acuity, but even with ≤20/200 at
baseline, recovery to ≥20/40 occurs in 85%.38 It is
possible that other types of testing, such as measuring
contrast sensitivity, OCT of the peripapillary RNFL,
VEPs or MRI of the optic nerve could better
discriminate between patients likely and unlikely to
have permanent deficits in visual function after ON.
85
Optic Neuritis: A Review
●
Temporal optic disc pallor develops within 4–6 weeks
from the onset of ON and the RAPD may disappear
when visual recovery is full.
Acute Therapeutic Options for ON
A meta-analysis of 12 randomized, controlled trials
of corticosteroid treatment in both patients with
ON and MS confirmed that although high-dose
intravenous corticosteroids were effective in
improving short-term visual recovery, there was no
statistically significant benefit in long-term outcome,39
even in those presenting with severe visual loss.
Corticosteroids do cause side-effects, both minor,
such as insomnia, weight gain and mood alterations,
and major, including psychotic depression,
pancreatitis and osteonecrosis.27
Although routine treatment of typical demyelinating
ON with corticosteroids is not advised due to lack of
long-term benefit and the potential for side-effects,
there are specific situations where corticosteroids
may be offered to shorten the period of functional
impairment. Corticosteroids, therefore, are
considered for patients who require faster recovery,
such as monocular patients, patients with severe
bilateral visual loss, or those with occupations
requiring normal visual acuity. The recommended
regimen is 1 g of intravenous methylprednisolone
sodium succinate per day for three days, based on
the ONTT.25 An oral taper, however, is not normally
necessary as this short treatment is unlikely to
suppress the hypothalamic-pituitary axis.40 Review
within 1 month is recommended to ensure that vision
does not deteriorate after cessation of treatment.
Appropriate consent should be taken prior to
commencing corticosteroids.
Intravenous immunoglobulin (IVIG) treatment in
acute ON has been shown to have no beneficial
effect.41,42 There are no randomized prospective
studies evaluating the role of plasma exchange in
demyelinating ON and small studies of its use do not
conclusively demonstrate a visual improvement
beyond that expected from its natural history.43
However, this would not be surprising if, as
suggested, more severe cases such as NMO were
included in the series.
At present, there is no treatment that can reverse
established poor visual outcome after typical
demyelinating ON.
86
Risk of Recurrence of ON
Optic neuritis can recur either in the same or the
contralateral eye. The ONTT has shown that 28%44
and 35%7 of patients developed recurrence of ON
within 5 and 10 years, respectively. Not surprisingly,
recurrence was more common in patients who were
subsequently diagnosed with MS. In the ONTT the risk
of recurrence of ON at 5 years was found to be
higher in the oral prednisolone (1 mg/kg) group
(41%) when compared with those who received
intravenous methylprednisolone or placebo (25%).45
At 10 years this higher risk between the
prednisolone-treated (44%) and intravenous group
(29%) had persisted,7 but was no longer statistically
significant (P=0.07). It is unclear whether this result
should lead to a cessation in the use of oral
prednisolone in acute ON as the effect has not been
confirmed in other studies and was only statistically
significant at an early time-point in the ONTT.
Furthermore, this outcome measure was not one of the
planned primary or secondary measures of the
ONTT,46 has no definitive biological explanation and
should be viewed critically as a likely chance finding.
It is also unclear whether the use of high-dose oral
corticosteroids would also increase the risk of recurrent
ON.47 A small prospective controlled clinical trial of
oral methylprednisolone (500 mg/day for five days)
showed no increase in the rate of demyelinating
attacks.48
Risk of Developing MS
Multiple sclerosis is a clinical diagnosis based on the
dissemination of typical lesions of the CNS in time
and space. The ONTT reported that the risk of
development of MS after an episode of isolated
unilateral ON is 38% at 10 years1 and 50% at 15
years.49 Another study reported that 54% of patients
with ON go on to develop MS after 30 years.13 Up
to 75% of female patients and 35% of male patients
initially presenting with ON ultimately develop MS.50
In children the risk of MS following an episode of
demyelinating ON is much lower than in adults and
estimated to be 26% after 40 years.21
The most significant contribution of imaging in
the setting of demyelinating ON is in imaging the
brain. This is due to the fact that the most valuable
predictor for the development of subsequent MS is
the presence of white matter abnormalities. In a
patient with demyelinating ON, the presence of even
a single, 3 mm-diameter, T2-signal lesion seen on
The International MS Journal 2009; 16: 82–89
●
MRI increases the probability that additional
neurological manifestations sufficient for a diagnosis
of MS will develop.51
In the ONTT, the 5-year risk of developing MS was
16% in patients with normal brain MRI findings,
37% with 1–2 lesions and 51% with three or more
lesions. At 10 years, the only statistically significant
difference was between no lesions (22% risk) and
one or more lesions (56% risk),1,7,44 which at 15
years had risen to 25% and 75% respectively.49,52
The mean time to diagnosis in patients who
subsequently developed MS was 3 years. However,
among patients with brain lesions seen on MRI, the
10- and 15-year probability of remaining free of
MS was 44% and 25% respectively. Conversely,
even in the absence of brain lesions the risk of
developing MS was 22% and 25% at 10 and
15 years respectively.
In a similar study which looked at the predictive
role of MRI lesions, but with fewer patients and lower
follow-up rate, after 10 years MS was present in
83% of those with MRI lesions at enrolment and in
11% of those without.53,54
Other than lack of MRI findings, being male,
having papillitis, vision of no light perception, lack
of pain, retinal exudates and peripapillary
haemorrhages are associated with a lower risk
of developing MS.1,7,44
In the ONTT at 2-year follow-up of patients with
acute ON and two or more lesions on MRI, the
intravenous-methylprednisolone therapy group (versus
placebo and oral prednisone groups) showed a
significantly decreased risk of developing MS.
However, this benefit was not maintained at
3 years29,55,56 and is of doubtful significance.
Moreover, as mentioned above, this outcome
measure was not one of the planned primary or
secondary measures of the ONTT.
DMDs
Magnetic resonance imaging evidence of dissemination
of lesions of the CNS in time and space is sufficient for
the diagnosis of MS even before clinical dissemination
has occurred according to the McDonald diagnostic
criteria.57 When MRI was repeated at 3 months in
patients presenting with a clinically isolated syndrome
(CIS), the McDonald criteria were found to have a
specificity of 93% and a positive predictive value of
83% for the development of clinically definite MS
(CDMS) at 3 years.58
The International MS Journal 2009; 16: 82–89
Optic Neuritis: A Review
Pathological and MRI studies suggest that axonal
damage occurs early on during the course of MS
which will result in permanent neurological
impairment.59–61 This issue is at the centre of the
debate over whether early intervention with DMDs in
CIS, especially those with high-risk features for
developing MS, can delay progression to CDMS.62
To date, there are three randomized, double-blind,
placebo-controlled trials using interferon beta 1-a and
1-b in patients with CIS, such as ON, who have at
least two or more white matter lesions on brain MRI.
All three studies: the Controlled High-Risk Avonex®
MS Study (CHAMPS),63–65 the Early Treatment of
MS (ETOMS) study66 and the Betaferon® in Newly
Emerging MS For Initial Treatment (BENEFIT) study,67
demonstrated that interferon beta increases the time
interval to a second MS-defining relapse in high-risk
patients at 1–5 years. Patients in the interferon group
also had significantly fewer lesions on brain MRI than
did those in the placebo group. This effect is identical
to the known effect of these treatments in relapsingremitting MS, where the number of relapses is reduced
by one-third, although here expressed as the time
interval between the first and second relapses. In
deciding whether or not to recommend such treatment
after a first episode of demyelinating ON it should be
remembered that over 40% of patients with abnormal
MRI scans at baseline will not go on to have a second,
MS-defining, episode at 10 years; also, these
treatments are only partially effective: the patient needs
to be treated for about 6 years in order to prevent one
relapse68 and finally, the long-term visual prognosis is
favourable even if MS develops.2
Practical Help and Advice
Despite the fact that many patients presenting with
ON for the first time will not develop MS, patients
should be made aware of this association by the
clinician. A fully informed discussion with the patient
about their individual risk of developing MS, together
with the availability of DMDs, can facilitate a
decision about whether to organize a brain MRI. It is
also crucial to emphasize that the patient may never
develop MS.
Despite evidence that the majority of patients
recover good vision based on objective parameters,
many patients commonly complain of residual deficits
in vision,69 colour vision,70 contrast sensitivity and
difficulty with depth and motion perception, the latter
due to the Pulfrich phenomenon. Symptomatic relief
87
Optic Neuritis: A Review
●
can be afforded by spectacles with one tinted lens in
front of the unaffected eye to balance the delay in
conduction from the other side.71 Patients can
alleviate Uhthoff’s phenomenon by remaining indoors
on hot and humid days and drinking plenty of cool
fluids, but principally they need to be reassured that
Uhthoff’s symptoms are entirely reversible and not
damaging to vision.
For patients who experience permanent visual
impairment following ON a wide range of low-vision
aids are available and formal psychological and
emotional support are offered for people coming to
terms with visual problems.
Conflicts of Interest
No conflicts of interest were declared in relation to
this article.
Address for Correspondence
Gordon T Plant, Box 93,
The National Hospital for Neurology &
Neurosurgery, London WC1N 3BG, UK
E-mail: [email protected]
Received: 26 May 2008
Accepted: 5 December 2008
References
Conclusions
A thorough history-targeted ophthalmic and neurological
examination of a patient presenting with painful
unilateral visual loss should help to clinically identify those
with typical demyelinating ON. Conditions which mimic
demyelinating ON should be considered and atypical
features promptly investigated. Specific neuroimaging
and other laboratory studies must be directed by the
clinical history and examination. When rapid visual
recovery is desirable, intravenous methylprednisolone
can be considered after discussion of possible side-effects
and with the patient bearing in mind that treatment does
not alter the final visual outcome.
The presence of any number of white matter
lesions on brain MRI at first presentation in acute
demyelinating ON can identify those at high risk of
developing MS in the future; it may be appropriate
to offer these individuals DMDs as prophylaxis,
according to local protocols and following full
discussion with the patient. Other high-risk clinical
characteristics and natural-history information can aid
in estimating a patient’s individual 10-year risk for
MS being the final diagnosis, bearing in mind that
even when MRI lesions are present 40% will not
develop CDMS within 10 years.
88
1. Beck RW, Trobe JD, Moke PS
et al. High- and low-risk profiles
for the development of multiple
sclerosis within 10 years after
optic neuritis: experience of the
optic neuritis treatment trial. Arch
Ophthalmol 2003; 121:
944–949.
2. Optic Neuritis Study Group.
Visual function 15 years after
optic neuritis: a final follow-up
report from the Optic Neuritis
Treatment Trial. Ophthalmology
2008; 115: 1079–1082.
3. Cleary PA, Beck RW, Anderson
MM et al. Design, methods, and
conduct of the Optic Neuritis
Treatment Trial. Control Clin
Trials 1993; 14: 123–142.
4. Kidd DP: Inflammatory optic
neuropathies not associated with
multiple sclerosis. In: Neuroophthalmology (Kidd DP,
Newman NJ, Biousse V, eds).
Boston: Butterworth Heinemann
2008; pp153–190.
5. Kidd DP, Plant GT. Optic neuritis.
In: Neuro-ophthalmology (Kidd
DP, Newman NJ, Biousse V, eds).
Boston: Butterworth Heinemann
2008; pp134–152.
6. Plant GT. Optic neuritis and
multiple sclerosis. Curr Opin
Neurol 2008; 21: 16–21.
7. Beck RW, Gal RL, Bhatti MT et
al. Visual function more than
10 years after optic neuritis:
experience of the optic neuritis
treatment trial. Am J Ophthalmol
2004; 137: 77–83.
8. Costello F, Coupland S, Hodge
W et al. Quantifying axonal loss
after optic neuritis with optical
coherence tomography. Ann
Neurol 2006; 59: 963–969.
9. Fisher JB, Jacobs DA, Markowitz
CE et al. Relation of visual
function to retinal nerve fiber
layer thickness in multiple
sclerosis. Ophthalmology 2006;
113: 324–332.
10. Trip SA, Schlottmann PG, Jones
SJ et al. Retinal nerve fiber layer
axonal loss and visual
dysfunction in optic neuritis. Ann
Neurol 2005; 58: 383–391.
11. Henderson AP, Trip SA,
Schlottmann PG et al. An
investigation of the retinal nerve
fibre layer in progressive multiple
sclerosis using optical coherence
tomography. Brain 2008; 131:
277–287.
12. Kurtzke JF. Optic neuritis or
multiple sclerosis. Arch Neurol
1985; 42: 704–710.
13. Rodriguez M, Siva A, Cross SA
et al. Optic neuritis: a populationbased study in Olmsted County,
Minnesota. Neurology 1995;
45: 244–250.
14. Phillips PH, Newman NJ, Lynn
MJ. Optic neuritis in African
Americans. Arch Neurol 1998;
55: 186–192.
15. Kurtzke JF. Multiple sclerosis
among immigrants. Br Med J
1976; 1: 1527–1528.
16. Dean G, Elian M. Age at
immigration to England of Asian
and Caribbean immigrants and
the risk of developing multiple
sclerosis. J Neurol Neurosurg
Psychiatry 1997; 63: 565–568.
17. Balcer LJ. Clinical practice. Optic
neuritis. N Engl J Med 2006;
354: 1273–1280.
18. Boomer JA, Siatkowski RM.
Optic neuritis in adults and
children. Semin Ophthalmol
2003; 18: 174–180.
19. Brady KM, Brar AS, Lee AG
et al. Optic neuritis in children:
clinical features and visual
outcome. J AAPOS 1999; 3:
98–103.
20. Morales DS, Siatkowski RM,
Howard CW et al. Optic neuritis
in children. J Pediatr Ophthalmol
Strabismus 2000; 37: 254–259.
21. Lucchinetti CF, Kiers L, O'Duffy A
et al. Risk factors for developing
multiple sclerosis after childhood
optic neuritis. Neurology 1997;
49: 1413–1418.
22. Schneck ME, HaegerstromPortnoy G. Color vision defect
type and spatial vision in the
optic neuritis treatment trial.
Invest Ophthalmol Vis Sci 1997;
38: 2278–2289.
The International MS Journal 2009; 16: 82–89
●
23. Goldstein JE, Cogan DG.
Exercise and the optic neuropathy
of multiple sclerosis. Arch
Ophthalmol 1964; 72: 168–170.
24. Optic Neuritis Study Group. The
clinical profile of optic neuritis.
Experience of the Optic Neuritis
Treatment Trial. Arch Ophthalmol
1991; 109: 1673–1678.
25. Beck RW, Cleary PA, Anderson
MM Jr et al. A randomized,
controlled trial of corticosteroids
in the treatment of acute optic
neuritis. The Optic Neuritis Study
Group. N Engl J Med 1992;
326: 581–588.
26. Hickman SJ, Ko M, Chaudhry F
et al. Optic neuritis: An update
typical and atypical optic
neuritis. Neuroophthalmology
2008; 32: 237–248.
27. Hickman SJ, Dalton CM, Miller
DH et al. Management of acute
optic neuritis. Lancet 2002; 360:
1953–1962.
28. Brass SD, Zivadinov R, Bakshi R.
Acute demyelinating optic
neuritis: a review. Front Biosci
2008; 13: 2376–2390.
29. Beck RW, Cleary PA, Trobe JD
et al. The effect of corticosteroids
for acute optic neuritis on the
subsequent development of
multiple sclerosis. The Optic
Neuritis Study Group. N Engl J
Med 1993; 329: 1764–1769.
30. Rolak LA, Beck RW, Paty DW
et al. Cerebrospinal fluid in acute
optic neuritis: experience of the
optic neuritis treatment trial.
Neurology 1996; 46: 368–372.
31. Cole SR, Beck RW, Moke PS
et al. The predictive value of CSF
oligoclonal banding for MS 5
years after optic neuritis. Optic
Neuritis Study Group. Neurology
1998; 51: 885–887.
32. Wu GF, Schwartz ED, Lei T et al.
Relation of vision to global and
regional brain MRI in multiple
sclerosis. Neurology 2007; 69:
2128–2135.
33. Balcer LJ, Baier ML, Cohen JA
et al. Contrast letter acuity as a
visual component for the Multiple
Sclerosis Functional Composite.
Neurology 2003; 61:
1367–1373.
34. Baier ML, Cutter GR, Rudick RA
et al. Low-contrast letter acuity
testing captures visual dysfunction
in patients with multiple sclerosis.
Neurology 2005; 64: 992–995.
35. Beck RW: Optic neuritis. In:
Miller NR and Newman NJ.
Walsh and Hoyt's Clinical
Neuro-ophthalmology, 5th edn
(Miller NR, Newman JJ, eds).
Baltimore: Williams & Wilkins
1998; pp599–647.
36. Beck RW, Trobe JD. What we
have learned from the Optic
Neuritis Treatment Trial.
Ophthalmology 1995; 102:
1504–1508.
37. Beck RW, Cleary PA. Recovery
from severe visual loss in optic
neuritis. Arch Ophthalmol 1993;
111: 300.
38. Kupersmith MJ, Gal RL, Beck RW
et al. Visual function at baseline
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
and 1 month in acute optic
neuritis: Predictors of visual
outcome. Neurology 2007; 69:
508–514.
Brusaferri F, Candelise L. Steroids
for multiple sclerosis and optic
neuritis: a meta-analysis of
randomized controlled clinical
trials. J Neurol 2000; 247:
435–442.
Wenning GK, Wietholter H,
Schnauder G et al. Recovery of
the hypothalamic-pituitaryadrenal axis from suppression by
short-term, high-dose intravenous
prednisolone therapy in patients
with MS. Acta Neurol Scand
1994; 89: 270–273.
Roed HG, Langkilde A,
Sellebjerg F et al. A double-blind,
randomized trial of IV
immunoglobulin treatment in
acute optic neuritis. Neurology
2005; 64: 804–810.
Noseworthy JH, O'Brien PC,
Petterson TM et al. A randomized
trial of intravenous
immunoglobulin in inflammatory
demyelinating optic neuritis.
Neurology 2001; 56:
1514–1522.
Ruprecht K, Klinker E, Dintelmann
T et al. Plasma exchange for
severe optic neuritis: treatment of
10 patients. Neurology 2004;
63: 1081–1083.
Optic Neuritis Study Group. The
5-year risk of MS after optic
neuritis. Experience of the Optic
Neuritis Treatment Trial.
Neurology 1997; 49:
1404–1413.
Optic Neuritis Study Group.
Visual function 5 years after optic
neuritis: experience of the Optic
Neuritis Treatment Trial. Arch
Ophthalmol 1997; 115:
1545–1552.
Goodin DS. Perils and pitfalls in
the interpretation of clinical trials:
a reflection on the recent
experience in multiple sclerosis.
Neuroepidemiology 1999; 18:
53–63.
Kaufman DI, Trobe JD,
Eggenberger ER et al. Practice
parameter: the role of
corticosteroids in the
management of acute
monosymptomatic optic neuritis.
Report of the Quality Standards
Subcommittee of the American
Academy of Neurology.
Neurology 2000; 54:
2039–2044.
Sellebjerg F, Nielsen HS,
Frederiksen JL et al. A
randomized, controlled trial of
oral high-dose
methylprednisolone in acute optic
neuritis. Neurology 1999; 52:
1479–1484.
Bhatti MT; Group ONS. The final
15-year follow-up report on the
neurological outcome of the
Optic Neuritis Treatment Trial.
34th Annual Meeting of the
North American NeuroOphthalmology Society
(NANOS), Orlando, USA,
2008.
The International MS Journal 2009; 16: 82–89
Optic Neuritis: A Review
50. Rizzo JF 3rd, Lessell S. Risk of
developing multiple sclerosis after
uncomplicated optic neuritis: a
long-term prospective study.
Neurology 1988; 38: 185–190.
51. Barkhof F, Filippi M, Miller DH
et al. Comparison of MRI criteria
at first presentation to predict
conversion to clinically definite
multiple sclerosis. Brain 1997;
120(Pt 11): 2059–2069.
52. Keltner J, Johnson C, Cello K
et al. A 15-year summary of
abnormal visual fields in the
Optic Neuritis Treatment Trial.
34th Annual Meeting of the
North American NeuroOphthalmology Society
(NANOS), Orlando, USA,
2008.
53. Brex PA, Ciccarelli O, O'Riordan
JI et al. A longitudinal study of
abnormalities on MRI and
disability from multiple sclerosis.
N Engl J Med 2002; 346:
158–164.
54. O'Riordan JI, Thompson AJ,
Kingsley DP et al. The prognostic
value of brain MRI in clinically
isolated syndromes of the CNS.
A 10-year follow-up. Brain 1998;
121(Pt 3): 495–503.
55. Beck RW, Arrington J, Murtagh
FR et al. Brain magnetic
resonance imaging in acute optic
neuritis. Experience of the Optic
Neuritis Study Group. Arch
Neurol 1993; 50: 841–846.
56. Beck RW, Smith CH, Gal RL et
al. Neurologic impairment 10
years after optic neuritis. Arch
Neurol 2004; 61: 1386–1389.
57. McDonald WI, Compston A,
Edan G et al. Recommended
diagnostic criteria for multiple
sclerosis: guidelines from the
International Panel on the
diagnosis of multiple sclerosis.
Ann Neurol 2001; 50:
121–127.
58. Dalton CM, Brex PA, Miszkiel KA
et al. Application of the new
McDonald criteria to patients
with clinically isolated syndromes
suggestive of multiple sclerosis.
Ann Neurol 2002; 52: 47–53.
59. Revesz T. Axonal lesions in
multiple sclerosis: an old story
revisited. Brain 2000; 123(Pt 2):
203–204.
60. De Stefano N, Narayanan S,
Francis GS et al. Evidence of
axonal damage in the early
stages of multiple sclerosis and its
relevance to disability. Arch
Neurol 2001; 58: 65–70.
61. Bermel RA, Puli SR, Rudick RA
et al. Prediction of longitudinal
brain atrophy in multiple sclerosis
by gray matter magnetic
resonance imaging T2
hypointensity. Arch Neurol 2005;
62: 1371–1376.
62. Frohman EM, Racke M, van Den
Noort S. To treat, or not to treat:
the therapeutic dilemma of
idiopathic monosymptomatic
demyelinating syndromes. Arch
Neurol 2000; 57: 930–932.
63. CHAMPS Study Group.
Interferon beta-1a for optic
64.
65.
66.
67.
68.
69.
70.
71.
neuritis patients at high risk for
multiple sclerosis. Am J
Ophthalmol 2001; 132:
463–471.
Beck RW, Chandler DL, Cole SR
et al. Interferon beta-1a for early
multiple sclerosis: CHAMPS trial
subgroup analyses. Ann Neurol
2002; 51: 481–490.
Kinkel RP, Kollman C, O'Connor
P et al. IM interferon beta-1a
delays definite multiple sclerosis
5 years after a first
demyelinating event. Neurology
2006; 66: 678–684.
Comi G, Filippi M, Barkhof F
et al. Effect of early interferon
treatment on conversion to
definite multiple sclerosis: a
randomised study. Lancet 2001;
357: 1576–15.82
Kappos L, Polman CH, Freedman
MS et al. Treatment with
interferon beta-1b delays
conversion to clinically definite
and McDonald MS in patients
with clinically isolated
syndromes. Neurology 2006;
67: 1242–1249.
Ghosh A, Kelly SP, Mathews J
et al. Evaluation of the
management of optic neuritis:
audit on the neurological and
ophthalmological practice in the
north west of England. J Neurol
Neurosurg Psychiatry 2002; 72:
119–121.
Frederiksen JL, Sorensen TL,
Sellebjerg FT. Residual symptoms
and signs after untreated acute
optic neuritis. A one-year followup. Acta Ophthalmol Scand
1997; 75: 544–547.
Cleary PA, Beck RW, Bourque LB
et al. Visual symptoms after optic
neuritis. Results from the Optic
Neuritis Treatment Trial. J
Neuroophthalmol 1997; 17:
18–23; Quiz, 24–28.
Heron G, Thompson KJ, Dutton
GN. The symptomatic Pulfrich
phenomenon can be successfully
managed with a coloured lens in
front of the good eye--a long-term
follow-up study. Eye 2007; 21:
1469–1472.
89