By Dr Piyush Ojha , DM Resident, GMC Kota under guidance of Prof. Dr Vijay Sardana (HOD,Neurology)

1. OPTIC NEURITIS
DR. PIYUSH OJHA
DM RESIDENT
DEPARTMENT OF NEUROLOGY
GOVT MEDICAL COLLEGE, KOTA

2. • Acute, non-infectious, inflammatory, demyelinating condition
• Causes acute, usually monocular, visual loss.
• Highly associated with MS
– Presenting feature in 15-20% cases
– Present during anytime in illness in 50%
• Female preponderance (2/3 cases)
• Usually between 20-40 yrs age
• Annual incidence in US = 6.4/lakh population

3. • Optic neuritis can be defined as :
– Typical - associated with multiple sclerosis,
improving independent of steroid treatment
– Atypical - not associated with multiple sclerosis,
steroid-dependent improvement.
• Causes of atypical optic neuritis include connective
tissue diseases (eg, SLE), vasculitis, sarcoidosis, or
neuromyelitis optica.

4. PATHOPHYSIOLOGY
• Most common pathology – inflammatory demyelination of
optic nerve.(similar to that of acute multiple sclerosis (MS)
plaques in the brain)
• Perivascular cuffing, edema in the myelinated nerve sheaths,
and myelin breakdown.
• Inflammation of the retinal vascular endothelium can precede
demyelination and is sometimes visibly manifest as retinal
vein sheathing .
• Myelin loss exceeds axonal loss.

5. • Hypothesized - Immune –mediated demyelination.
• Specific mechanism and target antigen(s) are unknown.
• Systemic T cell activation is identified at symptom onset and
precedes changes in the CSF.
• Systemic changes also normalize earlier (within 2-4 weeks)
than central changes.
• T cell activation leads to the release of cytokines and other
inflammatory agents.

6. • B cell activation against myelin basic protein
– not seen in peripheral blood
– but can be demonstrated in the CSF.
• As with MS, a genetic susceptibility for optic neuritis is
suspected , supported by an over-representation of certain
human leukocyte antigen (HLA) types among patients with
optic neuritis.

7. CLINICAL FEATURES
• Usually monocular presentation.
• In 10% cases- B/L symptoms can occur , either simultaneously
or in rapid succession.
• Bilateral optic neuritis - common in children < 12 - 15 yrs and
also in Asian and black South African patients .
• Since bilateral symptoms are relatively uncommon – should
search an alternative cause of optic neuropathy.

8. • However, subclinical visual deficits in acuity, contrast
sensitivity, color vision, and visual field in the contralateral eye
can often be elicited by detailed visual testing in patients with
clinically monocular disease .
• Contralateral eye deficits usually resolve along with the
clinical deficits in the symptomatic eye, it is unlikely that these
findings represent prior episodes of optic neuritis.

9. • Most common symptoms - Vision loss and Eye pain.
• Vision loss typically develops over a period of hours to days,
peaking within 1 - 2 weeks.
• Continued deterioration after that time - consider an
alternative diagnosis .
• Eye pain - 92% of patients in the ONTT and often worsened
with eye movement .
• Onset of pain generally coincided with the visual acuity loss
and improved along with it.

10. Other common visual symptoms and signs include:
• An afferent pupillary defect always occurs in optic neuritis if
the other eye is uninvolved and otherwise healthy.
• Visual field defect in optic neuritis – typically a central
scotoma.
• However, in the ONTT, almost all types of visual field defects
were seen, including diffuse vision loss and altitudinal,
arcuate, hemianopic, and centrocecal defects.

11. • A defect extending to the periphery should suggest a
compressive lesion.
• An altitudinal defect, particularly an inferior altitudinal defect,
is more common in anterior ischemic optic neuropathy .
• Visual field defects usually resolve;
– in the ONTT, 56% had normalized at one year and
– 73% had normalized at 10 years .
• Papillitis with hyperemia and swelling of the disk, blurring of
disk margins, and distended veins is seen in one-third of
patients with optic neuritis .

12. • 2 / 3 patients - retrobulbar neuritis with a normal fundus.
• Peripapillary hemorrhages are rare in optic neuritis, but are a
common accompaniment to papillitis due to anterior ischemic
optic neuropathy .
• Photopsias often precipitated with eye movement .(30% of
patients in the ONTT).
• Loss of color vision out of proportion to the loss of visual
acuity is specific to optic nerve pathology.
• Abnormal color vision by Ishihara plates
– 88 % of involved eyes in the ONTT;
– 94 % with the more sensitive Farnsworth-Munsell 100 hue
test .

13. • Other signs of ocular inflammation may be observed on
fundus or slit lamp examination.
• Perivenous sheathing or periphlebitis retinae can be seen in
about 12% patients.(high risk for MS)
• Uveitis, cells in the anterior chamber, and/or pars planitis are
uncommonly seen in optic neuritis and are more typical of
infections and other autoimmune diseases.

14. CHRONIC FEATURES
• Even after clinical recovery, signs of optic neuritis can persist.
• These signs in a patient without a history of optic neuritis may
suggest a previous, subclinical attack.
• Significance in a patient presenting with a possible first attack
of MS elsewhere in the CNS –as evidence of other
demyelinating episodes separated in "time and space" can
affect prognosis and treatment decisions.

15. Chronic signs of optic neuritis can include:
• Persistent visual loss
– Most patients recover functional vision within 1 year.
– However, on testing, deficits in color vision, contrast
sensitivity, stereo acuity, and light brightness are
detectable in most patients up to 2 years.
• A RAPD remains in approximately 25% patients 2 years after
presentation .

16. • Color desaturation defined as a qualitative inter-eye
difference in color perception that can be tested by
comparing vision of a red object with each eye. A patient with
monocular "red desaturation" may report that the red color
appears "washed out," pink, or orange when viewed with the
affected eye.
• Temporary exacerbations of visual problems in patients can
occur with increased body temperature (Uhthoff's
phenomenon).(Hot showers and exercise -classic precipitants)

17. • Optic atrophy to at least some degree almost always follows
an attack of optic neuritis, despite the return of visual acuity .
(Normal 20/20 visual acuity requires < 1/2 of normal foveal
axons)
• The disc appears shrunken and pale , particularly in its
temporal half (Temporal pallor).(often develops 4-6 weeks
after onset of visual loss)
• The pattern-shift visual evoked response remains delayed in
most patients, even with visual recovery.
– Although latencies continue to improve up to 2 years after
presentation, abnormalities are seen in 80% at two years.

18. Optic Neuritis : Fundus appearance

19. Optic Atrophy : Fundus appearance

20. DIFFERENTIAL DIAGNOSIS
• Young child - infectious and postinfectious causes
• older patient (>50 years) - ischemic optic neuropathy (eg. DM
or giant cell arteritis) is a more likely diagnosis than optic
neuritis.

21. DIAGNOSIS
• Optic neuritis is a clinical diagnosis based upon the history
and examination findings.
• A detailed ophthalmologic examination - an essential feature
of the clinical evaluation.
• Diagnostic testing directed toward excluding other causes of
visual loss in atypical cases and in assessing the risk of
subsequent multiple sclerosis (MS).

22. MRI
• MRI of the brain and orbits with gadolinium contrast
– confirmation of the diagnosis of acute demyelinating optic
neuritis and
– important prognostic information regarding the risk of
developing MS.
• Optic nerve inflammation can be demonstrated in about 95 %
of patients.

23. Orbit (A) and Coronal (B) Post-gadolinium T1-weighted MRI with fat suppression
demonstrating retrobulbar enhancement of optic nerve (white arrows)

24. • The longitudinal extent of nerve involvement as seen on MRI
correlates with visual impairment at presentation and with
visual prognosis.
• Gadolinium enhancement persists for a mean of 30 days since
onset.
• The signal abnormality in the nerve can still be seen after
recovery of vision, and is also present in approx 60% of
patients with MS who do not have a clinical history of optic
neuritis.

25. • The brain MRI often shows white matter abnormalities
characteristic of MS.
• Typical lesions - ovoid, periventricular, and larger than 3 mm.
• The reported prevalence of white matter abnormalities varies
substantially among patients with optic neuritis (23 - 75 %).

26. • In monosymptomatic or CIS cases, MRI provides prognostic
information.
• MRI T2 hyperintensities suggestive of demyelination stratifies
to higher MS risk:
• 5 yr risk – 50%
• 10 yr risk – 60%
• 15 yr risk – 70%
• Normal MRI stratifies to low MS risk :
• 5 yr risk – 15%
• 10 yr risk – 20%
• 15 yr risk – 25%

27. • Normal MRI with the following features define extremely low
MS-risk cohort (no MS case at 15 yrs) :
– Painless optic neuritis
– No light perception vision at onset
– Severe disc edema or disc hemorrhage
– Macular star figure exudate

28. LUMBAR PUNCTURE
• Not considered an essential diagnostic test in optic neuritis.
• Should be considered in atypical cases
– B/L presentation
– <15 years in age or
– symptoms suggesting infection
• Approximately 60 - 80 % patients - nonspecific abnormalities
in CSF, including lymphocytes (10 to 100) and elevated
protein.

29. • Other CSF findings in optic neuritis can include :
– Myelin basic protein in about 20 %
– IgG synthesis in 20 - 36 %
– Oligoclonal bands (OCB) in 56 - 69 %
• The presence of OCB implies a higher risk of developing MS.
• However, since OCB are also associated with white matter
lesions on brain MRI – role as independent prognostic marker
unknown .

30. • The ONTT concluded that routine blood tests including ESR,
ANA, and ACE levels, chest x-ray and serologic and CSF tests
for Lyme disease and syphilis are of no value in typical cases :
– Young patient with subacute vision loss and painful eye
movement.
• Thorough assessment considered in the presence of atypical
feature :
– Very swollen optic nerve
– Retinal exudates
– Absence of pain
– Absence of any recovery within 30 days

31. • Fluorescein angiography
– Not routinely performed.
– Often normal.
– 25 % demonstrate either dye leakage or perivenous
sheathing.
– These findings may identify patients at somewhat higher
risk for developing MS.

32. Visual evoked response (VER)
• A delay in the P100 of the VER is the electrophysiologic
manifestation of slowed conduction in the optic nerve as a
result of axonal demyelination.
• Not usually helpful in the diagnosis of acute optic neuritis,
unless there is a suspicion that the visual loss is functional.
• Abnormalities in the VER can persist after recovery of full
vision.
• 80 - 90 % will be abnormal at 1 year;
• 35 % will return to normal at 2 years.

33. • VER - often employed to find evidence of previous,
asymptomatic episodes of optic neuritis, but the sensitivity
and specificity are imperfect.

34. Optical coherence tomography (OCT) —
• Measures the thickness in the retinal nerve fiber layer
• Detects thinning in most (85 %) of patients with optic
neuritis.
• Lower values correlate with impaired visual outcome.
• However, its utility as a prognostic tool is limited in that
abnormal values do not show up until early swelling
disappears.
• In one study, OCT was less sensitive than VER in detecting
subclinical optic neuritis.
• Various studies have found that a greater severity of
optic nerve injury seen on OCT suggests Neuromyelitis
optica rather than optic neuritis associated with MS.

35. Aquaporin-4-specific serum autoantibody
• Patients with recurrent optic neuritis - at risk
Neuromyelitis optica or Devic's disease.
• Particularly true for patients with a normal brain MRI and
those with optic neuritis events in rapid succession.
• In one study, seropositivity for the aquaporin-4-specific
serum autoantibody was predictive of subsequent NMO
among patients with recurrent optic neuritis.
• This test has been suggested for individuals with
recurrent ON, particularly if MRI is negative.

36. TREATMENT
• Treatments aims
– To improve vision
– Preventing or ameliorating the development of
multiple sclerosis (MS).

37. OPTIC NEURITIS TREATMENT TRIAL (ONTT)
• Enrolled 457 patients between July 1988 to June 1991.
• Inclusion Criteria :
– A diagnosis of acute unilateral optic neuritis with visual
symptoms of < 8 days
– Age 18-46 years
– No previous history of optic neuritis or ophthalmoscopic
signs of optic atrophy in the affected eye
– No evidence of any systemic disease that may be
associated with optic neuritis
– No previous treatment with corticosteroid for optic
neuritis in the fellow eye

38. CORTICOSTEROIDS
• Patients in the Optic Neuritis Treatment Trial (ONTT) were
randomly assigned to:
– Oral Prednisone (1mg/kg/day) for 14 days with a four-day
taper;
– I/V Methylprednisolone (250mg 4 times/day for 3 days)
followed by oral prednisone (1mg/kg/day) for 11 days with
a four-day taper; or
– oral placebo for 14 days.
• Patients were treated within eight days of symptom onset.
• The primary visual outcomes were visual acuity and contrast
sensitivity.

39. • I/V Methyl Prednisolone
– accelerated the recovery of visual function; however
1-year visual outcomes were similar among treatment
groups.
– reduced the risk of conversion to MS within the first two
years in comparison with either placebo or
oral prednisone (7.5 vs 14.7 and 16.7 %).
– Among patients with > 2 white matter lesions on MRI,
incidence rates for MS were 16.2 versus 32.4 and 35.9
percent. N
– No differences in the rates of MS between treatment
groups at 5 years .

40. • The oral Prednisone arm of the study was found to have a
higher 2-year risk of recurrent optic neuritis in both eyes,
when compared with intravenous steroid therapy or with
placebo (30 vs 13 and 16 %).
• At 10 years, the risk of recurrent optic neuritis remained
higher in the oral prednisone group when compared with the
intravenous-treated group (44 vs 29 %)
• But there was no longer a significant difference between the
oral prednisone and placebo groups.

41. • The most common side effects associated with
Corticosteroids in the ONTT were :
– mood changes
– facial flushing
– sleep disturbances
– weight gain, and
– dyspepsia.

42. • A small randomized trial found that
oral Methylprednisolone 500mg for five days had a beneficial
effect on visual function at 1 and 3 weeks compared with
placebo.
• No differences between treatment groups with regard to
visual outcome at eight weeks or to the risk of developing
additional demyelinating events at one year.

43. • A decision to treat with intravenous steroids should be made
after considering all potential benefits and risks, with the
understanding that long-term visual outcome is not affected
by this treatment.

44. Other Acute Immunomodulatory therapy
• Alternative treatments include intravenous immunoglobulin
(IVIG) and plasma exchange.
• No established efficacy in the treatment of optic neuritis.
• Two randomized trials studied the potential benefit of IVIG in
55 and 68 patients with optic neuritis.
• Neither study found a difference in visual outcomes at six
months.
• MRI outcomes and the incidence of subsequent
demyelinating events at six months were also similar
between treatment groups.

45. CHRONIC IMMUNOMODULATORY THERAPY
• An important clinical decision in patients with optic neuritis is
whether or not to begin chronic immunomodulatory therapy
in order to prevent, delay, or ameliorate subsequent MS.
• The results from 3 randomized trials support the use of
treatment in high-risk patients, as defined by MRI findings.

46. Controlled High-Risk Avonex MS Prevention
Study (CHAMPS)
• Randomized, placebo-controlled trial of 383 patients with
clinically isolated syndromes (192 with optic neuritis)
• compared early treatment with Interferon beta-1a (Avonex),
30 µg intramuscularly each week versus placebo.
• Eligible patients were btwn 18 and 50 years, with two or more
demyelinating lesions on their brain MRI.
• All patients had received treatment with I/V MPS within 14
days after symptom onset and began study therapy within
four weeks (median time to therapy was 20 days).

47. • IFN beta-1a significantly reduced the 3-year cumulative risk of
developing MS (35 vs 50 %).
• Smaller number of T2-weighted and T1-gadolinium enhancing
lesions on brain MRI in the treated versus placebo group at 18
months.
• The total volume of T2 lesions on MRI was also smaller in the
treated group.
• Follow-up was extended to 5 years in a subset of willing
CHAMPS participants (53 %) . (CHAMPIONS)
• At 5 years, the cumulative risk of MS was lower among those
originally assigned to IFN beta-1a (immediate treatment)
compared with those originally assigned to placebo (delayed
treatment) (36 vs 49 %).

48. Early Treatment of Multiple Sclerosis Study (ETOMS)
• 308 patients with a first clinical demyelinating event
(98 - optic neuritis) - randomly assigned to IFN beta-1a , 22 µg
subcutaneously each week or to placebo.
• Inclusion criteria - either at least four white matter lesions or
three lesions with at least one demonstrating gadolinium
enhancement.
• Treatment began within three months of symptom onset.
• 70 % of the patients received treatment with corticosteroids
before starting interferon.

49. • At two years, a lower proportion of the interferon-treated
patients developed MS in comparison with placebo
(34 vs 45 %)
• The time to occurrence of the next demyelinating event was
longer in the treated versus placebo group (569 vs 252 days)
• Fewer treated patients had new T2-weighted lesions on brain
MRI compared with placebo.

50. • In the BENEFIT trial, 487 patients presenting with a clinically
isolated syndrome (CIS) (80 with optic neuritis) and at least
two lesions on brain MRI were assigned to receive 250 µg
interferon-1b subcutaneously or placebo every other day.
• At two years, the risk of developing clinically definite MS
– 45 % in the placebo group
– 28 % in the treatment group.
• The time for 25 % of patients to develop clinically definite MS
was delayed by about one year in the treated group.
• Treated patients had a lower cumulative number of new T2-
weighted lesions on brain MRI compared with the placebo
group.

51. • In the PreCISe study, 481 patients presenting with CIS and two
or more lesions on brain MRI were randomized to receive
either 20 mg Glatiramer acetate subcutaneously or placebo
each day.
• At 3 years - relative 45 % reduction in risk of conversion to
clinically definite MS.
• At 2 years - treated patients had a lower cumulative number
of new T2-weighted lesions on brain MRI compared with the
placebo group.
• The data from these studies indicate that early treatment in
patients with clinically isolated syndromes, including optic
neuritis, reduces the rate of MS development.

52. • Common side effects of beta interferon treatment in these
trials included depression, injection site reactions, and flu-like
symptoms.
• A significant number of patients on interferon therapy also
develop elevated liver enzymes.
• Therefore, liver function and other laboratory tests should be
checked prior to starting therapy and repeated every 3 and 6
months.

53. TREATMENT IN CHILDREN
• All of the clinical trials of treatment discussed above were
limited to adults.
• No clinical trial data are available to guide the treatment of
children with optic neuritis.
• Intravenous MPS can be considered for acute treatment for
severe debilitating bilateral vision loss in hopes of hastening
recovery.

54. • Final visual outcome is not altered by this treatment similar to
adults.
• In general, immunomodulatory treatments with interferons
are not used in younger children, although older children (>15
years) are probably appropriately treated under the same
guidelines as adults.

55. PROGNOSIS
• Prognostic concerns in patients with optic neuritis are
– visual recovery
– recurrence of optic neuritis, and
– risk of multiple sclerosis (MS).

56. • Recovery of vision —
– Without treatment, vision begins to improve after a few
weeks.
– Improvement can continue over many months; 90 % have
20/40 or better vision at one year.
– Some patients may have a more or less favorable
prognosis.
– Lower visual acuity at the time of presentation is
associated with less complete recovery; however, even
those who have no light perception at presentation can
recover normal vision.

57. – In the Optic Neuritis Treatment Trial (ONTT), 64 % of
patients whose vision at presentation was no better than
light perception achieved a final visual acuity of 20/40 or
better.
– Severe vision loss at one month, however, is less likely to
be associated with good visual recovery.
– Longer lesions in the optic nerve demonstrated on MRI,
particularly those extending into the optic canal, are
associated with poorer visual outcome.

58. • While most children with optic neuritis have a good visual
outcome, approximately 20 percent will have persistent
functional visual impairment.
• Patients with multiple sclerosis may have a somewhat less
favorable prognosis.
• Visual recovery is typically measured by acuity. However, one
study found that patients with recovery of full visual acuity
after optic neuritis may have persistent deficits in tasks that
require visual motion perception .

59. • Recurrence
– In the ONTT
• 35 % recurrence of optic neuritis at 10 years:
– 14 % in the original eye
– 12 % in the other eye and
– 9 % in both eyes .
– Individuals with recurrent optic neuritis have a greater risk
of developing MS.
– Seropositivity for the aquaporin-4-specific serum
autoantibody was predictive of subsequent NMO among
patients with recurrent optic neuritis in one study.

60. • Risk of multiple sclerosis
– In the ONTT , following a first episode of idiopathic
demyelinating optic neuritis
• the 5-year incidence of clinically definite MS was 30 %.
• incidence increased to 40 % at 12 years and
• 50 % at 15 years.
– The median time to diagnosis of MS was three years.
– Other series have reported similar results.

61. Clinical and laboratory features at the time of presentation
with optic neuritis are also helpful in determining prognosis:
• MRI abnormalities.
– The presence of characteristic demyelinating lesions on
MRI is a strong predictor of developing MS.
– In the ONTT, the risk of MS after 15 years was
• 72 % among those with one or more lesions on MRI
versus
• 25 % among those with no lesions.
– No significant risk difference between those with single
versus multiple lesions.

62. – No patient developed MS after 10 years of follow-up if
they had no white matter lesions on brain MRI along with
any one of the following clinical features considered
atypical for optic neuritis:
• no pain
• no light perception vision at presentation
• severe disc swelling
• peripapillary hemorrhage or
• retinal exudates.

63. • MRI findings also predict future MS-related disability.
• In one prospective series of 106 patients with optic neuritis,
the presence of
• baseline gadolinium-enhancing lesions, and
• the presence and number of infratentorial and spinal cord
lesions were predictive of disability among those who
developed MS .

64. • Recurrent episode of optic neuritis.
– Recurrent optic neuritis is more common among those
destined to develop MS.
– Patients with recurrent optic neuritis may be particularly at
risk for neuromyelitis optica or Devic's disease.
– Particularly true for patients with a normal brain MRI and
those with optic neuritis events in rapid succession .
– In one study, seropositivity for the aquaporin-4-specific
serum autoantibody was predictive of subsequent NMO
among patients with recurrent optic neuritis.
– Simultaneous bilateral involvement of the optic nerves at
the initial presentation, however, is associated with a
lower risk of MS in most but not all studies.

65. • Funduscopic examination —
– The presence of papillitis, especially if severe, is associated
with a lower risk of MS, particularly among those with
normal brain MRI .
– Retinal perivenous sheathing is not a common finding in
optic neuritis but when present does suggest a higher risk
of MS.

66. • Cerebrospinal fluid —
– Most studies conclude that individuals who have OCB in
the CSF at the time of the optic neuritis event are at higher
risk of developing MS.
– However, OCB are also associated with the presence of
white matter lesions on MRI and may not represent an
independent risk factor.
– The combination of a normal brain MRI and absent OCB
identifies individuals at very low risk of MS.

67. • Human leukocyte antigen —
– The human leukocyte antigen (HLA) type has been
reported to affect the relationship between optic neuritis
and MS.
– One prospective study of patients with optic neuritis found
a higher risk for conversion to MS among those with HLA-
DR2 alleles .
– Some investigations have corroborated this association,
but others have not.

68. • Serum antibodies —
– In one case series of 103 individuals with CIS (40 were
optic neuritis), seropositivity for antibodies against myelin
basic protein(MBP) and myelin oligodendrocyte
glycoprotein identified patients at high risk for MS.
– However, subsequent studies did not find this association
in a patient population with optic neuritis only.

69. REFERENCES
• Bradley’s Textbook of Neurology 6th edition
• Acute Optic Neuritis : AAN, Neurology 2015
• Current options for treatment of Optic Neuritis : John et al :
Clin Ophthalmology 2012
• Managements of Optic Neuritis : Vimla Menon et al: Indian
Journal of Ophthalmology 2011
• The Optic Neuritis Treatment Trial : Journal of Neuro-
Ophthalmology 1995
• www.uptodate.com