REVIEW

Review

Management of acute optic neuritis

S J Hickman, C M Dalton, D H Miller, G T Plant
Optic neuritis is a common condition that causes reversible loss of vision. It can be clinically isolated or can arise as
one of the manifestations of multiple sclerosis. Occasional cases are due to other causes, and in these instances
management can differ radically. The treatment of optic neuritis has been investigated in several trials, the results of
which have shown that corticosteroids speed up the recovery of vision without affecting the final visual outcome. Other
aspects of management, however, are controversial, and there is uncertainty about when to investigate and when to
treat the condition. Here we review the diagnostic features of optic neuritis, its differential diagnosis, and give practical
guidance about management of patients. The conditions association with multiple sclerosis will be considered in the
light of studies that define the risk for development of multiple sclerosis and with respect to results of trials of diseasemodifying drugs in these individuals.
Optic neuritis is common, having an incidence of 15 per
100 000 per year.13 The incidence is highest in
caucasians,4 in countries at high latitudes,2 and in spring.5
Individuals aged 2049 years are most at risk, with women
more often affected than men.2 The condition usually
presents as subacute unilateral loss of vision, although loss
of vision in both eyes can arise, either simultaneously or
sequentially. Most instances of optic neuritis are due to
idiopathic inflammatory demyelination, which can arise in
isolation, or as a manifestation of multiple sclerosis.6
Despite some major studies there are still many
controversial areas in the management of optic neuritis,
with differences of opinion expressed in surveys done to
investigate the way the condition is managed.7,8 In this
Review, we discuss the diagnosis and management of optic
neuritis, including the role of specialised investigations to
exclude other causes of visual loss that can mimic optic
neuritis. We will also discuss ways of identifying cases that
are corticosteroid-dependent and how to manage them.
The association of optic neuritis with multiple sclerosis will
be assessed, as will the role of investigations to define the
risk of development of multiple sclerosis. The results of
trials of disease-modifying drugs in those at risk of
development of multiple sclerosis, and how to advise
patients about that risk, will also be discussed.

Optic neuritis
Clinical features
Panel 1 shows the typical presenting symptoms and signs
of optic neuritis.9 The condition usually presents as a
painful subacute unilateral loss of vision, which progresses
over a few days to 2 weeks.10 In 10% of individuals, no pain
is reported4,10 and in the rest, the pain varies in severity,
although typically does not interfere with sleep (G T Plant,
unpublished). Light flashes (phosphenes or photopsias)
Lancet 2002; 360: 195362
NMR Research Unit, Institute of Neurology, University College
London, London, UK (S J Hickman MRCP, C M Dalton MRCPI,
Prof D H Miller FRCP); Neuro-Ophthalmology Department, Moorfields
Eye Hospital, London (S J Hickman, C M Dalton, G T Plant FRCP); and
The National Hospital for Neurology and Neurosurgery, London
(G T Plant)
Correspondence to: Dr G T Plant, Box 111, The National Hospital for
Neurology and Neurosurgery, London WC1N 3BG, UK
(e-mail: gordon@plant.globalnet.co.uk)

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might be seen by the patient on eye movement.11 Clearly,

subclinical cases are frequent, since some patients present
with Uhthoffs phenomenon (visual deterioration on
getting warm, or during exercise),12 and delayed visual
evoked potentials are not uncommon in early multiple
sclerosis, even without a previous history of optic neuritis.13
The maximum visual loss varies from minor blurring to
no perception of light in the affected eye. Abnormal colour
vision, reduced contrast sensitivity, visual field loss, and a
relative afferent pupillary defect (RAPD) are usually
present in the affected eye.4,10,14 The presence of an RAPD
is a useful objective sign of a unilateral optic neuropathy,
although it is not specific for optic neuritis. The absence of
an RAPD can indicate mild clinical involvement in the
affected eye, previous optic neuritis in the contralateral
eye, or subclinical optic neuropathy in the contralateral
eye.15
Slit lamp examination occasionally reveals cells in the
anterior chamber or vitreous, but is usually normal.16
However, intermediate uveitis, pars planitis, panuveitis,
and granulomatous uveitis are all associated with optic
neuritis and multiple sclerosis. The uveitis can be present
for some years before the onset of optic neuritis or multiple
sclerosis.17,18 The optic disc appears swollen in 3658% of
patients at presentation (figure 1).4,10 Small flame-shaped
haemorrhages or pronounced swelling of the optic disc
with cotton wool spots on the disc are seen occasionally. In
instances in which there is no disc swelling, the condition
is often labelled retrobulbar neuritis. Retinal examination
is usually unremarkable. However, in a series of 50
consecutive patients with optic neuritis,16 peripheral retinal
periphlebitis (perivenous sheathing) was seen in six
patients and fluoroscein leakage in ten. The presence of

Search strategy
This review is based on reading of neuro-ophthalmology
textbooks and on a search of PubMed for articles on optic
neuritis. Treatment trials were identified by searching PubMed
with the search terms: treatment of, corticosteroids, and
optic neuritis. Articles on diseases mentioned as part of the
differential diagnosis of optic neuritis were identified by
searching PubMed for the appropriate condition. Only articles
in English were used. The articles were selected to support the
discussion and to present evidence-based features of our own
practice.

1953

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REVIEW

Panel 1: Typical symptoms and signs of optic neuritis

Typical symptoms
Periocular pain and pain on eye movement
Pain could precede onset of visual symptoms
Progressive visual loss over a few days
Phosphenes or photopsias (spontaneous flashes of light in
vision) provoked by eye movement
Previous history of multiple sclerosis or previous neurological
symptoms
Spontaneous improvement in vision
Uhthoffs phenomenon (usually not noticed until the recovery
phase)
Fading of vision (usually not noticed until the recovery phase)
Pulfrichs effect (usually not noticed until the recovery phase)
Typical signs
Decreased visual acuity
Decreased colour vision
Decreased contrast sensitivity
Any type of visual field defect
Relative afferent pupillary defect
Normal or swollen optic disc
Normal macula and peripheral retina
Uveitis or retinal periphlebitis might be detected

these abnormalities was linked with an increased risk for

subsequent development of multiple sclerosis.16 Retinal
periphlebitis can also be seen in multiple sclerosis in the
absence of optic neuritis and is sometimes so severe as
to cause retinal ischaemia and peripheral retinal neovascularisation.19 Whether or not eyes affected by optic
neuritis show a higher incidence of retinal periphlebitis
than do eyes of patients with multiple sclerosis, which
have not been affected by optic neuritis, is not known.
Recovery
Pain associated with optic neuritis rarely lasts more than a
few days, and vision generally deteriorates over a few days
to 2 weeks before spontaneous improvement takes place.9
In the placebo group of the North American Optic
Neuritis Treatment Trial (ONTT),9 79% and 93% of
individuals had begun to show signs of improvement
within 3 weeks and 5 weeks of onset, respectively. The

initial period of recovery is rapid and probably relates to

the resolution of acute inflammation, and the conduction
block so caused, in the optic nerve.20 Further
improvement in vision is seen up to a year after the acute
episode.9 Remyelination and the proliferation of sodium
channels in demyelinated segments of the nerve to restore
conduction could be responsible for this recovery.21
Remyelination can continue for up to 2 years, as
suggested by progressive shortening of initially prolonged
visual evoked potential latencies, although after the first
year, remyelination is not usually associated with
functional improvement in vision.22 Reorganisation of
cortical activation has also been reported after optic
neuritis and could be involved in the recovery process.23
The mean visual acuity at 1 year after entry into the
ONTT was better than 6/5 (Snellen equivalent), with less
than 10% having a visual acuity worse than 6/12.9
Severity of the initial visual loss does seem to be related
to final visual outcome, but most patients recover well. Of
187 patients with visual acuity worse than 6/60 on
admission to ONTT, only 6% had this level of acuity or
worse at 6 months. Of 28 patients in whom visual acuity
was down to light perception, or worse, 64% recovered to
6/12 or better.24 In another group,25 of 12 patients who
presented with no light perception in the affected eye, five
recovered to 6/6 or better, three to 6/12 or better, and four
had peripheral recovery but dense central scotomata and
visual acuities of less than 3/60.
Other visual parameters tend to improve in parallel with
the improvement in visual acuity, but subjective residual
deficits are frequent.9 In one study26 of 58 patients, 59%
reported that their vision had not returned to normal
1 year after untreated optic neuritis, although only five
(8%) had a visual acuity in the affected eye worse than
6/9.26 Vision after optic neuritis can vary greatly during the
day and from one day to the next,27 and might deteriorate
in specific situationseg, Uhthoffs phenomenon,12 and
fatigue or fading of vision.28 Pulfrichs phenomenon
(misperception of the trajectory of moving objects) is
occasionally noted.29
The optic disc of patients usually becomes pale, either
diffusely or usually in the temporal region, despite
improvements in vision.9 The RAPD might disappear on
recovery, although, especially in instances in which there
is poor recovery, it can be persistent.

Differential diagnosis

Figure 1: Swollen optic disc due to optic neuritis

1954

Panel 2 shows the differential diagnoses of optic neuritis

and appropriate tests.9,3042 Misdiagnosis of optic neuritis
has been reported in clinical trials. Of 457 patients
enrolled in the ONTT, three were subsequently
diagnosed as having anterior ischaemic optic neuropathy,
two had compressive lesions (one ophthalmic artery
aneurysm and one pituitary tumour), and two had
connective tissue diseases in addition to optic neuritis.4,43
In a later study,44 of 102 patients enrolled, 17 were later
excluded due to misdiagnosis. The final diagnoses in
these patients included rhinogenic optic neuropathy
(sinus mucocoele), brain tumour, ischaemic optic
neuropathy, Lebers hereditary optic neuropathy,
nutritional optic neuropathy, and age-related macular
degeneration.
Presentation with severe pain that restricts ocular
movements or wakes the patient from sleep should alert to
the possibility of posterior scleritis37 or an infective or
granulomatous optic neuropathy, such as sarcoidosis or
chronic relapsing inflammatory optic neuropathy
(CRION).36,42 Visual loss in infective and granulomatous
optic neuropathy is usually more severe than in typical

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REVIEW

optic neuritis and does not spontaneously improve. In

instances of optic neuropathy due to sarcoidosis, there are
usually systemic features of the disease that can be
detected, although the condition might be restricted, at
least initially, to the optic nerve.42
Children or adults can present with a typical history for
optic neuritis, but on fundus examination swelling of the
optic disc and a macular star is seen, leading to the

diagnosis of neuroretinitis. This condition is usually

idiopathic, but can be associated with cat-scratch disease,
Lyme disease, syphilis, toxocariasis, toxoplasmosis, and
histoplasmosis.32 Prognosis for recovery is good and there
is no risk of development of multiple sclerosis.9 Sarcoid
optic neuropathy, if it affects the anterior optic nerve, can
cause disc swelling and a macular star,45 but spontaneous
recovery is unusual in sarcoidosis.

Panel 2: Differential diagnosis of optic neuritis9,3042

Diagnosis

Usual clinical features in each category

Tests to consider in each category

Corticosteroid-responsive optic neuropathies

Sarcoidosis
Progressive severe visual loss; may be
Systemic lupus erythematosus
very painful; often bilateral (simultaneous
Autoimmune optic neuritis
or sequential); isolated or as part of a
Chronic relapsing inflammatory optic
multisystem disorder; more frequent in Africans
neuropathy
or Afro-Caribbeans (sarcoidosis); relapse
Optic perineuritis
when corticosteroids withdrawn
Behets disease
Neuromyelitis optica (Devics disease)

MRI, orbits and brain with contrast

Lumbar puncture
ANA
Serum ACE
Chest radiograph
67
Gallium scan
Biopsy of accessible tissue (sarcoid)

Other inflammatory optic neuropathies

Post-infectious
Post-vaccination
Acute disseminated encephalomyelitis

Bilateral and simultaneous; often in

childhood; usually excellent prognosis

MRI, orbits and brain with contrast

Lumbar puncture

Swollen optic disc and macular star;

spontaneous recovery

Bartonella, borrelia, and syphilis

serology

Painless (rarely painfuleg, aneurysms and

mucocoeles); progressive visual loss;
optic atrophy at presentation; past history
of, or evidence for, primary tumour
(metastases)

CT or MRI, orbits and brain with

contrast
Biopsy if appropriate

Infectious optic neuropathies

Syphilis
Tuberculosis
Lyme disease
Viral optic neuritis

Progressive visual loss with exposure to

infectious agent; severe optic disc oedema
cellular reaction in vitreous

Appropriate serology
Lumbar puncture
Chest radiograph
Tuberculin test

Ischaemic optic neuropathies

Anterior ischaemic optic neuropathy
Posterior ischaemic optic neuropathy (PION)
Giant cell arteritis (GCA)
Diabetic papillopathy

Usually older age group; sudden onset;

painless (except GCA); swollen optic
disc (except PION); altitudinal field defect

Erythrocyte sedimentation rate

Bilateral and symmetrical; painless;

poor prognosis

Serum vitamin B12

Family history; sequential (or simultaneous)

bilateral painless; visual loss

Genetic testing for Lebers mutation

Severe pain; less visual symptoms

B-mode ultrasound of orbits

Neuroretinitis
Compressive optic neuropathies
Primary tumourseg, meningiomas,
gliomas, and pituitary tumours
Metastases
Tuberculomas
Thyroid ophthalmopathy
Arterial aneurysms
Sinus mucocoeles

Toxic and nutritional optic neuropathies

Vitamin B12 deficiency
Tobacco-alcohol amblyopia
Methanol intoxication
Ethambutol toxicity
Cuban and Tanzanian epidemic optic
neuropathies
Inherited optic neuropathies
Lebers hereditary optic neuropathy

Ocular causes
Posterior scleritis

Maculopathies and retinopathies, including Painless; metamorphopsia;

central serous retinopathy
preserved colour vision

Electroretinogram
Fluoroscein angiogram

Big blind spot syndrome and acute

zonal occult outer retinopathy

Electrocardiogram

Visual field loss and photopsias;

normal fundus; preserved colour vision

ACE=angiotensin converting enzyme. ANA=antinuclear antibodies. Metamorphopsia=distorted vision.

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REVIEW

Panel 3: Warning signs in the presentation of optic

neuritis that should prompt further investigation to
rule out alternative diagnoses
Optic atrophy on presentation without previous optic neuritis or
multiple sclerosis
Severe optic disc oedema with vitreous reaction
Optic disc haemorrhage
Bilateral loss of vision
Previous history of neoplasia
African or Afro-Caribbean patients with vision <6/12 and no
early recovery
Loss of vision to no perception of light with no early recovery
Painless loss of vision to <6/60 with no early recovery
Severe or persistent pain for >2 weeks since onset
Visual loss progressing for >2 weeks since onset of visual
symptoms
Absence of recovery >3 weeks after onset of visual symptoms
Deterioration of vision after withdrawal of corticosteroids

Diagnostic tests
Generally, optic neuritis can be diagnosed on clinical
grounds (panel 1). However, if any warning signs or
atypical features for optic neuritis arise, which are
suggestive of an alternative diagnosis (panel 3), further
investigations should be done promptly.32,46 The best
management of some conditionseg, optic nerve
compression by a sinus mucocoele, or a tuberculous or
granulomatous optic neuropathyrequires appropriate
treatment to be administered within days of
presentation; delay can result in a much worse visual
outcome. Thus, an expectant approach must not be
adopted if clinical features are atypical. Combined
ophthalmological and neurological services are helpful
in improving diagnostic accuracy, and early review is
important to ensure that visual recovery, either
subjectively or objectively, has begun since, if not, optic
neuritis is an unlikely diagnosis.
Investigations should be guided by the clinical
presentation (panel 2). Ready access to imaging facilities
is important. Contrast-enhanced high-resolution CT
with fine cuts through the orbits will show up most
compressive lesions.30 Short tau inversion recovery or
fat-saturated fast spin-echo MRI is preferable in that it
does not involve ionising radiation and can also show
any intrinsic optic nerve lesions, as arise in optic neuritis
(figure 2).47
Visual evoked potentials might not be helpful in
differentiating between different causes of optic
neuropathies in the acute phase,30 although the
combination of visual evoked potentials with pattern
electroretinogram (PERG) can be useful in

Figure 2: Fat-saturated proton-density fast spin-echo MRI of

left-sided acute optic neuritis
Arrow points to affected optic nerve.

1956

differentiating macular from optic nerve disorders. In

retinal disorders, both the P50 (early) and N95 (late)
components of the PERG are abnormal, whereas in
disorders of the optic nerve only the N95 component is
abnormal.30,48 In acute optic neuritis, however, the P50
can also be reduced in the acute phase, which
normalises during recovery.48 In clinical practice, the
presence of a delayed but well preserved P100 wave of
the visual evoked potential is most useful in confirming
a diagnosis of optic neuritis if the presentation is
delayed, or in supporting a diagnosis of multiple
sclerosis, by showing dissemination in space in
appropriately selected patients.49,50
If a corticosteroid-responsive optic neuropathy is
suspected, both conventional and gadolinium-enhanced
MRI of the orbits and brain should be done. In
sarcoidosis,
CRION,
and
optic
perineuritis,
enhancement of the optic nerve sheath is typical.36,40,51
Additionally,
in
sarcoidosis,
basal
meningeal
enhancement and enhancing cerebral lesions might be
seen.51 White-matter lesions on both T2-weighted and
gadolinium-enhanced MRI are usually seen in the
context of multiple sclerosis, however, the finding can
be non-specific. The importance of small T2
abnormalities alone requires a consideration of the site
and shape of the lesions and the age of the patient,
recognising that age-related changes due to small-vessel
disease should not be misinterpreted as evidence for
demyelination.52
Serological and other evidence for sarcoidosis,
vasculitis, and syphilis should be sought, and
tuberculosis considered in appropriate patients. In
instances of suspected infectious or corticosteroidresponsive optic neuropathy, a lumbar puncture should
also be done. Results of examination of the
cerebrospinal fluid can be used to look for infections,
hypercellularity, a raised protein concentration, and
local or systemic production of oligoclonal bands of
immunoglobulins to try to help differentiate between
demyelinating optic neuritis and other causes of
inflammatory optic neuritis. In optic neuritis there
might be no oligoclonal bands or local intrathecal
synthesis of immunoglobulins (unmatched bands
compared with serum). In CRION, sarcoidosis,
vasculitis, or acute disseminated encephalomyelitis there
might be no oligoclonal bands or systemic production of
immunoglobulins (matched oligoclonal bands in both
cerebrospinal fluid and serum).36,42

Treatment
Several trials have been done to attempt to improve the
prognosis of typical optic neuritis with respect to visual
outcome. Findings of early, observational studies10
suggested that corticosteroids might be effective,
although this view was controversial. Subsequent
placebo-controlled trials6,43,5363 of corticosteroids have
been done and are summarised in panel 4. A metaanalysis of these trials showed that corticosteroids
reduced the number of patients without clinical
improvement at 30 days (odds ratio 060,
range 042085), but did not result in long-term
improvement in visual outcome (096, 071131).64
When the presenting visual acuity was 6/12 or better,
corticosteroids conferred no benefit in the ONTT.43
There has been a suggestion that the absence of a longterm beneficial effect in the trials might be because the
corticosteroids were given too late to provide
neuroprotection.65 Treatment trials in the hyperacute
phase are required to address this issue.

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REVIEW

Panel 4: Randomised controlled trials of corticosteroids in acute unilateral optic neuritis

Study
Rawson et al,
196653
Rawson and
Liversedge,
196954

Entry criteria
Treatment to commence
within 10 days of onset
of symptoms

Treatment groups
1) IM ACTH 40 units/day for
30 days (n=25)
2) IM placebo for 30 days
(n=25)

Visual outcome
Faster recovery of VA in
treatment group (p<001
at 30 days) but no effect
at 1 year

Comments
All treated patients pain-free by
2 days
Placebo group pain-free
by 2 weeks

Bowden et al,
197455

Any patient irrespective

of delay to initiation
of treatment

1) IM ACTH 40 units/day
for 30 days (n=27)
2) IM placebo for 30 days
(n=27)

No significant treatment
effect for any visual
variable at any time up
to 2 years

Mean delay to treatment of

167 days (ACTH group) and
185 days (controls)

Gould et al,
197756

Treatment to commence 1) Retrobulbar triamcinolone

within 10 days. VA <6/9, 40 mg (n=31)
abnormal colour vision, 2) No injection (n=30)
RAPD, and central scotoma

Faster rate of recovery of

VA in treatment group
(p=01 at 1 week)
No difference seen at
2 and 6 months

Single blind

TrauzettalKlosinski et al,
199357

Randomisation within
21 days and before
recovery
RAPD and more than two
of: abnormal VA; central
scotoma; abnormal VEP
or flicker test, or both

1) Oral MPtapering dose

over 24 days starting at
100 mg/day (n=16)
2) Oral thiamine 100 mg/day
for 24 days (n=34)

Trend for all variables

Not all patients blinded to
tested to recover faster in treatment
the treated group, but with
no treatment benefit at
12 months

Optic Neuritis
Treatment
Trial6,43,58-60

Treatment to commence
within 8 days of onset
of symptoms
RAPD and abnormal
visual field in affected
eye

1) Oral prednisolone
1 mg/kg per day for 14 days
(n=156)
2) IV MP 250 mg QDS for
3 days then 1 mg/kg per day
prednisolone for 11 days
(n=151)
3 days of dose tapering
in both treatment groups
3) Oral placebo for 14 days
(n=150)

Median VA 6/75 by day 4

in IV MP group compared
with day 15 in other two
groups
Minimal treatment benefit
at 30 days and no effect
seen after 1 and 5 years
No treatment benefit from
IV MP if VA 6/12
No benefit shown for
prednisolone

No IV placebo group
Increased risk of recurrence of
ON after prednisolone at
5 years (p=0003 vs IV MP,
p=0004 vs placebo)
Decreased 2-year (ARR 034,
95% CI 016074) but not
3-year rate of CDMS after IV MP

Kapoor et al,
199861

Randomisation within
30 days
VA 6/9
Optic nerve lesions
classified as long
(15 mm) or short
on STIR MRI

1) IV MP 1 g per day for

3 days with no tapering
dose (n=33)
2) IV saline for 3 days
(n=33)

Trend for increased rate of

recovery of VA after IV MP
in all patients and in those
with long lesions
No effect seen at 6 months

No correlation between initial

VA and initial lesion length
Treatment did not affect
6 month lesion length on MRI

Sellebjerg et al, Treatment to commence

199962
within 28 days of onset
of symptoms
VA 07

1) Oral MP 500 mg per day

for 5 days with a tapering
dose for 10 days (n=30)
2) Oral placebo for 15 days
(n=30)

Improved spatial vision at

3 weeks in treatment
group (p=003)
No benefit after 8 weeks
and 1 year

MP did not affect the

conversion to CDMS at 1 year
(p=08)

Wakakura et al, Treatment to commence

within 14 days of onset
199963
of symptoms
RAPD in affected eye

1) IV MP 1 g per day for

3 days then oral taper for
710 days (n=33)
2) IV mecobalamin 500 g
per day for 3 days then
orally for 7 days (n=33)

Faster visual recovery for

all variables tested
after IV MP but no
treatment effect seen
after 12 weeks and 1 year

Mecobalamin treatment used

for comparison as placebo
treatment considered unethical
in Japan

ACTH=adrenocorticotropic hormone (corticotropin); ARR=adjusted rate ratio; CDMS=clinically definite multiple sclerosis; IM=intramuscular;
IV=intravenous; MP=methylprednisolone; ON=optic neuritis; QDS=4 times per day; RAPD=relative afferent pupillary defect; STIR=short tau inversion
recovery; VA=visual acuity; VEP=visual evoked potential.

Corticosteroids can cause side-effects. Frequent

minor side-effects reported include insomnia, mild
mood changes, stomach upsets, facial flushing, acne,
oedema, and weight gain.43,62 More serious side-effects
seen in the intravenous methylprednisolone group of the
ONTT (n=151) include one patient developing

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psychotic
depression
and
another
developing
pancreatitis.43 There have also been reports of avascular
necrosis (osteonecrosis) of the femoral head66 and deaths
in children due to chickenpox after short-term
corticosteroid therapy.67,68 There are currently no other
treatment options for acute demyelinating optic neuritis.

1957

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REVIEW

Recommendations for management

Optic neuritis
In 2000, the Quality Standards Subcommittee of the
American Academy of Neurology69 stated that oral
prednisolone in doses of 1 mg/kg/day has no demonstrated
efficacy in the recovery of visual function in acute
monosymptomatic optic neuritis, and therefore is of no
proven value in treating this disorder. Higher dose oral or
parenteral methylprednisolone or adrenocorticotrophic
hormone [corticotropin] may hasten the speed and degree
of recovery of visual function in persons with acute
monosymptomatic optic neuritis. There is, however, no
evidence of long-term benefit for visual function. The
decision to use these medications to speed recovery but not
to improve ultimate visual outcome should therefore be
based on other non-evidence-based factors such as quality
of life, risk to the patient, visual function in the fellow eye,
or other factors that the clinician deems appropriate.
When treatment is instigated, 1 g per day intravenous
methylprednisolone for 3 days has become the preferred
option.7 This option tends to be given as a single daily dose,
which enables outpatient treatment. In the USA, an oral
taper of prednisolone after this regimen remains popular,
although it is less often used in the UK and Europe.70 The
rationale for the use of an oral taper is concern with respect
to suppression of the hypothalamic-pituitary-adrenal axis,
although with the short treatment regimens used fast
recovery of the axis is seen and the oral taper should not
normally be needed.71 Another concern is that after
cessation of intravenous methylprednisolone symptoms can
deteriorate with recrudescence of inflammation, as has
been suggested by results of studies on the brain with serial
gadolinium-enhanced MRI in patients with multiple
sclerosis.72 However, there were no reports of recovery
followed by deterioration of vision in the one study that did
not use an oral taper.61 Furthermore, we have not noticed
worsening of vision after cessation of intravenous
methylprednisolone in our patients, except in instances
proven to have another causeeg, granulomatous optic
neuropathy.
Because of the lack of evidence of long-term benefit and
because of the potential for side-effects from corticosteroids, we do not routinely treat typical optic neuritis with
corticosteroids. However, if there is pre-existing poor vision
in the contralateral eye, we offer corticosteroids to shorten
the period of functional impairment. We give 1 g per day
intravenous methylprednisolone for 3 days without an oral
taper, but review early to ensure that vision does not
deteriorate after cessation of treatment. Appropriate
precautions are taken before starting treatment, and we
warn all patients of possible side-effects.73
If a corticosteroid-responsive optic neuropathy is
suspected, we start treatment with intravenous methylprednisolone 1 g per day for 3 days followed by 1 mg/kg per
day oral prednisolone. This dose is then slowly reduced
over 812 weeks. If a relapse occurs on reducing the dose,
high-dose treatment is reinstigated and a corticosteroidsparing agent such as azathioprine started before reducing
the dose again. That patients are instructed to report
immediately if deterioration in vision is noticed, is of
utmost importance. Protocols for osteoporosis prophylaxis
are followed. In optic neuritis associated with vasculitis
eg, in systemic lupus erythematosusthe visual outcome
may be improved if cyclophosphamide is given at an early
stage, but there are no published data to support this course
of action.
At present there is no treatment that can reverse
established poor visual outcome after typical optic neuritis.
An early report74 suggested that intravenous immuno-

1958

globulin might be helpful in promotion of remyelination

and improvement of vision. A larger subsequent trial75
randomised 55 patients with multiple sclerosis and
persistent visual acuity loss after optic neuritis to receive
either 04 g/kg intravenous immunoglobulin daily for
5 days followed by three single infusions monthly for
3 months, or placebo. The trial was terminated early
because of negative results; visual acuity was unchanged
after 6 months follow-up (p=0766), although there was a
trend for improvement after 12 months (p=0132). The
improvement was, however, modest, amounting to a mean
difference of two letters on the logMAR acuity chart, with
no improvement in visual evoked potential latency. The
absence of significant improvement in these patients could
imply that intravenous immunoglobulin does not induce
remyelination, or that irreversible disability could be largely
a result of axonal degeneration. Future therapies could
include neuroprotective agents,76 strategies to induce
remyelination,65 and optic nerve transplantation, although
all are at this time experimental.77
Bilateral optic neuritis
In instances of bilateral (simultaneous or early sequential)
optic neuritis we investigate and treat our patients as if they
had a corticosteroid-responsive optic neuropathy. We treat
with parenteral followed by oral corticosteroids to hasten
functional visual recovery, and follow patients up closely as
the oral prednisolone is tapered off to ensure that worsening
vision does not arise.
Childhood optic neuritis
Children more frequently have bilateral and simultaneous
optic neuritis than do adults,78 and the condition normally
arises after a viral infection.79 Visual recovery in childhood is
usually good. In one cohort,78 78% of participants had a
visual acuity of 6/6 or better after a mean follow-up of
88 years. Another series79 reported better prognosis for
unilateral optic neuritis than for bilateral cases, although
many of the bilateral cases had recurrent attacks of visual
loss.79 There have been no treatment trials of corticosteroids
in children with the condition. We usually follow a waitand-see policy for unilateral cases and bilateral cases with
minor visual loss. In a typical bilateral case with severe
visual loss we would not recommend further investigations,
but would advise treatment with 3 days of 15 mg/kg per day
intravenous methylprednisolone (equivalent to 1 g per day
in adults) without an oral taper but with close monitoring.
Risk of recurrence of optic neuritis
The cumulative probability of having recurrent optic
neuritis after 5-years of follow-up in the ONTT was 19%
for the affected eye, 17% for the unaffected eye, and 30%
for either eye.80 The risk of recurrence was twice as high in
patients who had developed multiple sclerosis, and was also
higher in those who were initially treated with oral
prednisolone. The cumulative probability of recurrence at
5 years was 41% in the prednisolone group, 25% in the
intravenous methylprednisolone group (p=0003), and
25% in the placebo group (p=0004). The increased risk
was apparent throughout follow-up, although there is not a
convincing explanation for the underlying mechanism
behind this association.

Optic neuritis and multiple sclerosis

The association between optic neuritis and multiple
sclerosis has been apparent for many years.10 Multiple
sclerosis is a clinical diagnosis based on the dissemination
of lesions of the central nervous system in time and
spaceie, the occurrence of a second clinical episode at a

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For personal use. Only reproduce with permission from The Lancet Publishing Group.

REVIEW

Panel 5: McDonald diagnostic criteria for multiple

sclerosis after optic neuritis
MRI dissemination in space, consisting of three out of four of
the following:

One gadolinium-enhancing lesion or nine T2 hyperintense

lesions if no enhancing lesions

At least one infratentorial lesion

At least one juxtacortical lesion

At least three periventricular lesions

(one spinal cord lesion can be substituted for one brain
lesion)
Baseline

or
Two or more MRI-detected lesions consistent with multiple
sclerosis plus positive cerebrospinal fluid (oligoclonal bands
different from any such bands in the serum, or the presence of
raised IgG index, or both)
and
MRI dissemination in time
First MRI 3 or more months after the clinical event
1. A gadolinium-enhancing lesion (not at the site
implicated in the first clinical event) is sufficient
evidence to indicate dissemination in time
2. If there are no gadolinium-enhancing lesions a
second scan is required more than 3 months later.
A new T2 or gadolinium-enhancing lesion is sufficient
evidence for dissemination in time

First MRI less than 3 months after the clinical event

1. A second MRI done 3 or more months after the optic
neuritis, showing a gadolinium-enhancing lesion is
sufficient evidence for dissemination in time
2. If no enhancing lesion is seen on this MRI, a further
scan done not less than 3 months after the first scan
that shows a new T2 or enhancing lesion will suffice

or
A second clinical attack

different site in the central nervous system. Clinically

definite multiple sclerosis can be diagnosed when the
episodes are confirmed by a neurologist without
supporting investigations.81 The risk of development of
multiple sclerosis after isolated instances of optic neuritis is
greater the longer the follow-up period is. In one series,3
the 10-year risk of clinically definite multiple sclerosis was
39%, the 20-year risk was 49%, the 30-year risk was 54%,
and the 40-year risk was 60%.3 The risk is increased in
women,82,83 in those with retinal vascular abnormalities,16 in
those who are HLA-DR2 positive,83,84 and in those who
have oligoclonal bands on examination of cerebrospinal
fluid.83,85 The risk of development of multiple sclerosis after
childhood and after bilateral simultaneous optic neuritis is
much lower.78,86
The strongest predictor for the development of multiple
sclerosis is the presence of asymptomatic white-matter
lesions on MRI of the brain. The 5-year risk of clinically
definite multiple sclerosis in the ONTT was 16% in
202 patients with no brain lesions, but 51% in the
89 patients with three or more lesions.6 In a different
cohort,87 clinically definite multiple sclerosis developed in
37 of 71 patients (52%) with one or more lesions after
10 years, whereas no patient with normal imaging
developed the disease. The risk of early multiple sclerosis
developing rises if asymptomatic spinal cord lesions, in
addition to brain lesions, are present at baseline. In a
study88 of patients with clinically isolated syndromes (CIS)
suggestive of multiple sclerosisie, optic neuritis, and

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3 months

Figure 3: MRI evidence of dissemination of central nervous

system lesions in time and space
Baseline proton-density weighted fast spin-echo MRI of a 37-year-old
woman with optic neuritis (left), showing asymptomatic brain lesions
(arrows), and gadolinium-enhanced T1-weighted spin-echo image taken
3 months later (right), showing two new enhancing lesions (arrows)
sufficient to give a diagnosis of multiple sclerosis based on the
McDonald criteria.

spinal cord and brain stem syndromesten of 21 (48%)

patients with abnormal brain and spinal cord imaging
developed multiple sclerosis at 1 year compared with three
of 17 (18%) with brain lesions alone. The risk of multiple
sclerosis within 1 year also increased if new brain lesions
were detected on repeat brain imaging after 3 months.
Multiple sclerosis arose in 12 of 21 (57%) patients with
new lesions on T2-weighted imaging and seven of
11 (64%) patients with new gadolinium-enhancing lesions,
but in only one of 20 (5%) patients who had abnormal
baseline imaging and no new lesions at 3 months.88
The International Panel on Multiple Sclerosis Diagnosis
has published diagnostic criteria for multiple sclerosis
(McDonald criteria),89 which suggest that MRI evidence of
dissemination of lesions of the central nervous system in
time and space is sufficient for the diagnosis of multiple
sclerosis even before clinical dissemination has occurred
(panel 5; figure 3). These criteria clarify the role of MRI in
clinical practice but have not been without controversy,
principally with respect to the reliance on imaging data
when the findings on MRI can be non-specific.90 However,
when applied to a cohort of CIS patients,91 the criteria
using repeat imaging after 3 months, had a specificity of
93% and a positive predictive value of 83% for the
development of clinically definite multiple sclerosis at
3 years.
Even if multiple sclerosis does develop after optic
neuritis, the prognosis for disability is usually good, being
associated with a benign course of the disease (odds
ratio 173, 95% CI 127235).92 After 5 years, only 17 of
105 patients who developed clinically definite multiple
sclerosis (4% of the entire cohort) in the ONTT had an
expanded disability status scale (EDSS) score of three or
more, and only five had an EDSS score of six or more,
although this finding did include one patient who died
from multiple sclerosis.6 As well as predicting an increased
risk for the development of multiple sclerosis, brain MRI
lesion load can also help to predict the probability of
development of disability after a CIS. In a cohort of
patients followed up for 14 years after a CIS,93 EDSS
correlated with both baseline lesion volume (r=048) and
change in lesion volume in the first 5 years (r=061),
suggesting that early inflammatory activity in multiple
sclerosis is related to the later development of disability.
Treatments to delay onset of multiple sclerosis
Are there any treatments that alter the risk for
development of multiple sclerosis after clinically isolated

1959

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REVIEW

optic neuritis? Results of a post hoc analysis from the

ONTT suggested that there was a decreased risk for the
development of clinically definite multiple sclerosis in
patients who received intravenous methylprednisolone
(n=10, 75%) compared with the risk in those who received
prednisolone (n=19, 147%) or placebo (n=21, 167%),
after a follow-up of 2 years in patients with clinically isolated
optic neuritis on entry to the study (n=389).59 The adjusted
rate ratio for the development of clinically definite multiple
sclerosis in the group on intravenous methylprednisolone
was 034 (95% CI 016074) compared with placebo.
Most of the treatment effect was seen in patients with an
abnormal brain MRI on entry to the trial. The findings,
however, were based on a retrospective analysis, using an
open-label treatment (there was no intravenous placebo
arm) with only small numbers developing multiple sclerosis.
Also, data were not available for 50 of the patients, which
could have had a confounding effect. The beneficial effect
was lost by 3 years, with a cumulative incidence of clinically
definite multiple sclerosis of 173% in the methylprednisolone group, 247% in the prednisolone group, and
213% in the placebo group.60 The importance of these
findings remains uncertain. If intravenous methylprednisolone delays the onset of clinically definite multiple
sclerosis, the effect is short-lived and does not affect either
the eventual risk of clinically definite multiple sclerosis or
the development of disability.6 In our opinion, intravenous
methylprednisolone should not be given in instances in
which the sole aim is to protect against multiple sclerosis;
treatment should be guided by the other factors outlined in
this Review.
Two trials94,95 have addressed whether interferon can
slow down the progression from CIS to clinically definite
multiple sclerosis. 383 patients were recruited to the
CHAMPS study94 after their first demyelinating event
(192 with optic neuritis) who, in addition, had two or more
clinically silent brain lesions on MRI.94 Half the patients
received intramuscular interferon -1a 30 g once a week
and half placebo. The trial was stopped early after an
interim analysis since the cumulative probability of the
development of clinically definite multiple sclerosis during
3-years follow-up was significantly lower in the interferon
group than in the placebo group (rate ratio 056;
95% CI 038081; p=0002). There was also a relative
reduction in new lesion activity on MRI in the interferon
group (p<0001). A similar group of patients (n=309, 98
with optic neuritis) was enrolled to the ETOMS study,95 but
four asymptomatic white matter lesions (or three if one was
enhancing after administration of gadolinium) were
required for entry. Half the patients received subcutaneous
interferon -1a 22 g once a week and half placebo. After
2 years, the odds ratio for conversion to clinically definite
multiple sclerosis was 061 (95% CI 037099; p=0045) in
the treatment group compared with the placebo group,
again with less new lesion formation in the treatment group
(p<0001). The treatments were well tolerated with no
excess major adverse events due to the interferons.
Significant minor adverse events included influenza-like
symptoms (both trials), depression (CHAMPS), and
reactions at the injection site (ETOMS).
These results are not surprising because in essence the
interferons reduce the relapse rate, which is a well known
effect in relapsing-remitting multiple sclerosis. These
patients were at high risk for the development of multiple
sclerosis in view of the abnormal baseline brain imaging
results. Pooling the results with results from studies in
relapsing-remitting multiple sclerosis, the interferons reduce
the relapse rate by a third. The annual relapse rate in these
patients is about 05 per year. Treatment with interferons,

1960

therefore, has to be given for 6 years to prevent one relapse

in this group of patients.96 There are also no long-term data
that can say whether, by reducing inflammatory activity, the
interferons prevent the development of disability due to
multiple sclerosis.
Recommendations for management
Brain MRI at presentation can give an indication of risk for
development of multiple sclerosis and, if a high lesion load
is present, give further information with respect to
probability of later disability, although the association is not
strong. Many patients with CIS and brain lesions have a
benign long-term course.93
In the UK, the Association of British Neurologists
guidelines recommend disease-modifying drugs only in
established multiple sclerosis. Brain imaging at presentation
with optic neuritis will not, therefore, alter initial treatment
decisions. In the absence of evidence that earlier treatment
of patients with CIS has a greater long-term effect on
prognosis for disability, our current practice is to treat only
ambulant patients with clinically active, established
relapsing-remitting multiple sclerosis, or secondary
progressive multiple sclerosis with superimposed disabling
relapses. In countries where disease-modifying drugs are
available for use after a CIS if asymptomatic brain lesions
are present, baseline brain imaging could be useful to guide
the treatment decision.
Repeat imaging of patients with CIS could establish an
earlier diagnosis of multiple sclerosis by use of the
McDonald criteria. In some patients, this early diagnosis
will enable a more informed discussion of diagnosis and
prognosis. Further studies are needed to ascertain whether
or not the subgroup of patients with CIS who develop
multiple sclerosis, according to the McDonald criteria, will
benefit from long-term treatment with disease-modifying
drugs.
That the diagnosis of optic neuritis is secure before
treatment with a disease-modifying drug begins is
important, since three patients with anterior ischaemic optic
neuropathy and incidental white matter lesions of presumed
vascular origin have been given interferon -1a on the
erroneous assumption that the cause of visual loss was optic
neuritis.97
Because the risk of multiple sclerosis after optic neuritis is
much lower in children than in adults, and since diseasemodifying drugs are not licensed for use in children, we do
not recommend routine brain imaging after either unilateral
or bilateral optic neuritis in this population unless required
for initial diagnosis.
What to tell the patient
There has been understandable reluctance to discuss the
link between optic neuritis and multiple sclerosis with
patients.8 An awareness of their risk of development of
multiple sclerosis can cause much anxiety, despite the fact
that many will not develop the disease. A previous diagnosis
of optic neuritis can, however, affect future insurance policy
applications, and many patients have discovered that they
are at risk of developing multiple sclerosis only when they
have had insurance applications refused. There is also a
wealth of information available on the internet, linking optic
neuritis with multiple sclerosis. Our policy is to discuss the
risks fully with all patients, emphasising that they might
never develop multiple sclerosis but that if they do the
prognosis can be good. The decision of whether to organise
initial or follow-up brain MRI should be guided by the
availability of disease-modifying drugs and by discussion
with the patients as to whether definitive diagnosis and risk
stratification is important to them.

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For personal use. Only reproduce with permission from The Lancet Publishing Group.

REVIEW

Conclusion
Optic neuritis is a self-limiting condition that can usually
be diagnosed on the basis of the clinical picture. Parenteral
corticosteroids can help to speed up visual recovery
without affecting the long-term prognosis for visual
function. An expectant approach to management is
therefore reasonable, although if there is suspicion of a
different diagnosis or deviation from the expected clinical
course then urgent investigations are called for to rule out,
in particular, a compressive lesion or a corticosteroidresponsive optic neuropathy. Furthermore, optic neuritis
can be the first manifestation of multiple sclerosis. An
increased risk of multiple sclerosis exists if there are
asymptomatic brain lesions on MRI. Serial MRI can
provide an early diagnosis of multiple sclerosis in some
patients. Although interferons can delay the time to a
second relapse, their long-term effect on disability is
unknown.
Contributors
G T Plant conceived the idea for the Review. S J Hickman wrote the first
draft, which was rewritten with extensive contributions from C M Dalton,
D H Miller, and G T Plant.

Conflict of interest statement

CMD is supported by Elan.

Acknowledgments
SJH is supported by The Wellcome Trust. CMD is supported by Elan.
The NMR Research Unit is supported by the Multiple Sclerosis Society of
Great Britain and Northern Ireland. Our sponsors played no role in the
writing of this review.

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