Transcript The Optic Neuritis Treatment Trial ( ONTT )

The Optic Neuritis Treatment
Trial ( ONTT )
R.R.Battu
Narayana Nethralaya
Bangalore
Classical Demyelinating Optic Neuritis
• Young adults between 20 and 45 years
• F:M = 3:1
• Monocular retro ocular pain particularly on eye movement (?
Upward)
• Followed several hours or a few days later by rapid visual loss
occurring over a few days to a week
• Clinical examination : Dyschromatopsia (mostly red/green) and loss
of contrast out of proportion to visual acuity loss.
• Afferent pupillary defect/RAPD
• Fundus shows either normal fundus or mild/moderate disc edema
• About 3 weeks later, visual acuity starts improving and continues to
improve over the next 6 months.
Typical Demyelinating Optic Neuritis
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Acute to subacute onset – progressive over a few days to 2 weeks
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Young adult patient, typically less than 45 years of age, but may be of any age
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Periocular pain (90%), especially with eye movement – preceding or coinciding
with visual loss
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Unilateral loss of visual acuity – variable severity
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Reduced contrast and colour vision – out of proportion to loss of visual acuity
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Exacerbation of symptoms with increased body temperature (Uhthoff’s
phenomenon)
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Normal (65%) or swollen (35%) optic nerve head MS
Typical Demyelinating Optic Neuritis
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Ipsilateral relative afferent pupillary defect
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Mild periphlebitis (venous sheathing)
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Visual field defect – almost any type
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Spontaneous visual improvement in >90% starting within 2–3 weeks
regardless of treatment
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No deterioration in vision when corticosteroids are withdrawn
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Pallor of the optic disc is seen within 4–6 weeks from onset of visual loss
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Ancillary investigations suggestive of MS
Atypical Optic Neuritis
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Age >50 or <12 years
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Bilateral simultaneous or rapidly sequential ON and chiasmitis
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Severe visual loss – no light perception
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Progressive visual loss for >2 weeks from onset
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Painless visual loss
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Pain following onset of visual loss or persistent pain for >2 weeks from onset
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Severe pain that restricts eye movements or wakes patient from sleep
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Unusual ocular findings: Marked anterior and/or posterior segment inflammation /
Marked periphlebitis (venous sheathing) /Markedly swollen optic nerve head / Marked
optic disc haemorrhages /Macular star
Atypical Optic Neuritis
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Lack of any visual recovery within 5 weeks or continued deterioration in visual
function
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Symptoms or signs of a systemic disorder other than MS
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African or Asian race
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Family history
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Corticosteroid-dependent optic neuropathy/ deterioration in vision when
corticosteroids are withdrawn
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Previous history of neoplasia
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Ancillary investigations suggestive of a diagnosis other than MS (NMO, sarcoidosis,
Behçet syndrome)
Differential Diagnosis of Optic Neuritis
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Corticosteroid-responsive optic neuropathies
– Sarcoidosis, systemic lupus erythematosus, Behçet syndrome, autoimmune ON, NMO, chronic
relapsing inflammatory optic neuropathy
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Other inflammatory conditions
– Post-infection, post-vaccination, neuroretinitis, acute disseminated encephalomyelitis
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Compressive optic neuropathies
– Primary tumours, gliomas, meningioma, pituitary tumours – particularly craniopharyngioma in
children, metastases, sinus mucocoeles, arterial aneurysms
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Ischaemic optic neuropathies
– Anterior and posterior ischaemic optic neuropathy, giant cell arteritis, diabetic papillopathy
Differential Diagnosis of Optic Neuritis
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Infective conditions
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Toxic and nutritional optic neuropathy
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Posterior scleritis, maculopathy, retinopathy, big blind spot syndrome
Periorbital infection
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Leber hereditary optic neuropathy
Ocular causes
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Vitamin B12 deficiency, tobacco-ethanol amblyopia, methanol intoxication, ethambutol toxicity
Inherited conditions
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Tuberculosis, syphilis, Lyme disease, viral ON, toxocariasis or helminthitis (usually visible retinal/optic head
lesion)
Cellulitis, severe suppurative sinusitis
Factitious visual loss
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Intentional or ‘hysterical’
Multiple Sclerosis ( MS )
• Schumacher Criteria – 1965 – clinical
• Poser Criteria – 1983 – MRI and spinal taps
• McDonald’s Criteria – 2001 – MRI and clinical
Multiple Sclerosis
Relapsing / Remitting Multiple
Sclerosis ( RRMS) ---- 55%
Primary Progressive Multiple
Sclerosis (PPMS) --- 15%
Secondary Progressive Multiple
Sclerosis (SPMS) ---- 30%
Progressive Relapsing Multiple Sclerosis
(PRMS) --- 5%
The Optic Neuritis Treatment Trial
Interventional (drug), randomised single blind placebo controlled trial
• To determine the natural history of vision in patients who
suffer optic neuritis.
• To assess the beneficial and adverse effects of corticosteroid
treatment for optic neuritis.
• To identify risk factors for the development of multiple
sclerosis in patients with optic neuritis.
Questions asked
(1) Does treatment with either oral prednisone
or intravenous methylprednisolone followed
by oral prednisone improve the visual
outcome of acute optic neuritis?
(2) Does either treatment speed recovery of
vision? and
(3) Are the complications of treatment
insignificant in relation to the magnitude of
the treatment effect?
• Treatment phase ( ONTT )
• Long term follow up phase ( Longitudinal optic
neuritis study [LONS] )
• Oral prednisone (1 mg/kg/day) for 14 days
– 156 patients randomised
• Intravenous methylprednisolone (250 mg every 6 hours) for 3 days,
followed by oral prednisone (1 mg/kg/day) for 11 days
– 151 patients randomised
• Oral placebo for 14 days
– 150 patients randomised
Follow up
• 7 follow up visits during the first 6 months
– Primary outcome at 6 months
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At one year
Yearly upto 1997
2001 – 2002
2006
Baseline and Follow up tests
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Neurological evaluation
Visual Acuity
Contrast
Colour
Fields
Vision specific quality of life questionnaire
• Parameters assessed
– Visual acuity ( BCVA ) --- Logmar for analysis
– Colour vision --- Ishihara and FM-100 Hue
– Visual fields --- Humphrey 30-2 and Goldman
– Contrast Sensitivity --- Pelli – Robson Chart
Classification of Changes on Brain
Magnetic Resonance Images
Graded 0 to 4 based on the following criteria
– Number of lesions
– Size and shape of lesions:
• <3 mm, > 3 mm, > 20 mm
– Location of lesions:
• periventricular, peripheral white matter, grey matter,
brainstem, cerebellum and corpus callosum
Baseline characteristics
• Eligibility criteria:
– 8 to 45 years
– unilateral optic neuritis, with visual symptoms of 8
days' duration or less
– relative afferent pupillary defect
– field defect in the affected eye
Ancillary Tests
• neurologic examination
• MRI
• glucose,antinuclear antibody [ANA], and
fluorescent treponemal antibody absorption
[FTAABS1] tests
• CXR
• MS classification by Poser’s classification
CSF evaluation and MRI
• The presence of oligoclonal bands in the CSF
strongly correlated with the future development
of MS
• However, the presence of oligoclonal bands
strongly correlated with an MRI positive for one
or more lesions
• THERE IS NO NEED TO DO A CSF ANALYSIS IN
CLASSICAL DEMYELINATING ON, HOWEVER, AN
MRI WOULD BE MANDATORY TO ASSESS
PROGNOSIS
Results
• 448 patients at entry …… 300 at 15 year f.u.
• M: F = 22.8% : 77.2% [ 1: 3 ]
• Age : 31.8 +/- 6.7 years
The Clinical Profile of Optic Neuritis
Experience of the Optic Neuritis Treatment Trial
Optic Neuritis Study Group
(Arch Ophthalmol. 1991;109:1673-1678)
Visual Acuity in ON
• Course of VA recovery
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79% start recovering in 3 weeks and 96% start recovery in 5 weeks
At 1 year: 93% had VA ≥ 20/40 and 69% had achieved 20/20
At 15 years: 92% had VA ≥ 20/40 and 72% had achieved ≥ 20/20
85% of patients with VA ≤ 20/200 at presentation had EVENTUAL VA of
≥ 20/40
In classical monocular demyelinating ON, VA recovery occurs soon and
most patients achieve normal or near normal vision. This is across all
treatment groups with no statistical difference between groups
The best predictor of EVENTUAL acuity was initial acuity
Final VA was worse in patients EVENTUALLY diagnosed as MS
The role of steroid
• THERE IS NO ROLE OF ORAL STEROID
– In the 5 year outcome studies, oral steroid use was significantly
associated with recurrent optic neuritis
• THERE IS A ROLE FOR IV METHYLPREDNISOLONE AND THIS
IS TO SHORTEN THE PERIOD OF RECOVERY
• THIS DOES NOT AFFECT FINAL VISUAL ACUITY
• THE INDICATIONS FOR IVMP IN CLASSICAL DEMYELINATING
ON
– MONOCULAR PATIENTS
– SEVERE BILATERAL VISUAL LOSS
– OCCUPATIONAL REQUIREMENTS
• ** REVIEW VA AFTER A MONTH – LACK OF IMPROVEMENT
MANDATES EVALUATION FOR OTHER CAUSES OF ON
Recurrence of ON
• 28% develop recurrence in 5 years, 35%
develop recurrence in 10 years
• At 5 (10) years, higher in the oral pred group
41% (44%), than in the placebo/IVMP group
25% (29%)
• More likely in patients who subsequently
diagnosed as MS
Risk of MS
• OVERALL –
– AT 10 YEARS ------ 38%
– AT 15 YEARS ------ 50%
• The influence of gender
– 35% of males and 75% of females ultimately develop
MS ( a non ONTT observation )
• The 2 year follow up study showed that IVMP has
a protective role in the development of MS, but
this was not significant after the 3rd year
MRI and risk of developing MS
• CIS – Clinically isolated event [ monocular
optic neuritis ]
• CDMS – Clinically definite MS
Without MRI findings
• At 5 years ----- 16%
• At 10 years ----- 22%
Only 3% increased
risk after 10 years
• At 15 years ------ 25%
With MRI findings
• At 5 years ----------
37% with 1-2 lesions
51% with ≥ 3 lesions
• At 10 years ------
56% with ≥ 1 lesion
20% increased risk after
10 years
• At 15 years ------
75% with ≥ 1 lesion
Protective factors
• Male gender
• Optic nerve head swelling [ papillitis ]
• Atypical presentation
– severe optic disc swelling
– Disc or peripapillary haemorrhages
– Retinal exudates
– Absent pain
– Vision no PL
Brief Bibliography
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PN Shams, GT Plant. Optic Neuritis: A Review
The International MS Journal 2009; 16: 82–89
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Multiple Sclerosis Risk after Optic Neuritis: Final Optic Neuritis Treatment Trial Follow-Up.
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The Optic Neuritis Study Group*. Arch Neurol. 2008 June ; 65(6): 727–732
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The Clinical Profile of Optic Neuritis. Experience of the Optic Neuritis Treatment Trial. Optic
Neuritis Study Group. Arch Ophthalmol. 1991;109:1673-1678
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Roy W. Beck, Robin L. Gal, Treatment of Acute Optic Neuritis. A Summary of Findings From
the Optic Neuritis Treatment Trial. ARCH OPHTHALMOL/VOL 126 (NO. 7), JULY 2008
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Long-term Brain Magnetic Resonance Imaging Changes After Optic Neuritis in Patients
Without Clinically Definite Multiple Sclerosis Optic Neuritis Study Group. Arch Neurol.
2004;61:1538-1541
ONTT
• The results of the ONTT are applicable to
monocular demyelinating typical optic neuritis
• Beware of applying these results to all cases
presenting with “optic neuritis”
• In general, the visual outcome is usually good
irrespective of treatment
• The MRI (T-2 weighted 1.5 Tesla ) is an
extremely important prognosticator for future
MS