The%20Optic%20Neuritis%20Treatment%20Trial%20(%20ONTT%20)

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The Optic Neuritis Treatment Trial ( ONTT )

• R.R.Battu
• Narayana Nethralaya
• Bangalore

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Classical Demyelinating Optic Neuritis

• Young adults between 20 and 45 years
• FM 31
• 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.

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Typical Demyelinating Optic Neuritis

• 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 (Uhthoffs phenomenon)
• Normal (65) or swollen (35) optic nerve head MS

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Typical Demyelinating Optic Neuritis

• Ipsilateral relative afferent pupillary defect
• Mild periphlebitis (venous sheathing)
• Visual field defect almost any type
• Spontaneous visual improvement in gt90 starting
  within 23 weeks regardless of treatment
• No deterioration in vision when corticosteroids
  are withdrawn
• Pallor of the optic disc is seen within 46 weeks
  from onset of visual loss
• Ancillary investigations suggestive of MS

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Atypical Optic Neuritis

• Age gt50 or lt12 years
• Bilateral simultaneous or rapidly sequential ON
  and chiasmitis
• Severe visual loss no light perception
• Progressive visual loss for gt2 weeks from onset
• Painless visual loss
• Pain following onset of visual loss or persistent
  pain for gt2 weeks from onset
• Severe pain that restricts eye movements or wakes
  patient from sleep
• 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

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Atypical Optic Neuritis

• 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)

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Differential Diagnosis of Optic Neuritis

• 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

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Differential Diagnosis of Optic Neuritis

• 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

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Multiple Sclerosis ( MS )

• Schumacher Criteria 1965 clinical
• Poser Criteria 1983 MRI and spinal taps
• McDonalds Criteria 2001 MRI and clinical

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Multiple Sclerosis
Secondary Progressive Multiple Sclerosis (SPMS)
---- 30
Relapsing / Remitting Multiple Sclerosis ( RRMS)
---- 55
Progressive Relapsing Multiple Sclerosis (PRMS)
--- 5
Primary Progressive Multiple Sclerosis (PPMS) ---
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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.

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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?

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• Treatment phase ( ONTT )
• Long term follow up phase ( Longitudinal optic
  neuritis study LONS )

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• 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

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Follow up

• 7 follow up visits during the first 6 months
• Primary outcome at 6 months
• At one year
• Yearly upto 1997
• 2001 2002
• 2006

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Baseline and Follow up tests

• Neurological evaluation
• Visual Acuity
• Contrast
• Colour
• Fields
• Vision specific quality of life questionnaire

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• 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

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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
• lt3 mm, gt 3 mm, gt 20 mm
• Location of lesions
• periventricular, peripheral white matter, grey
  matter, brainstem, cerebellum and corpus callosum

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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

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Ancillary Tests

• neurologic examination
• MRI
• glucose,antinuclear antibody ANA, and
  fluorescent treponemal antibody absorption
  FTAABS1 tests
• CXR
• MS classification by Posers classification

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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

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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

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The Clinical Profile of Optic Neuritis Experience
of the Optic Neuritis Treatment Trial Optic
Neuritis Study Group
(Arch Ophthalmol. 19911091673-1678)
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Visual Acuity in ON

• Course of VA recovery
• 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

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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

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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

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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

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MRI and risk of developing MS

• CIS Clinically isolated event monocular optic
  neuritis
• CDMS Clinically definite MS

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Without MRI findings

• At 5 years ----- 16
• At 10 years ----- 22
• At 15 years ------ 25

Only 3 increased risk after 10 years
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With MRI findings

• At 5 years ----- 37 with 1-2 lesions
• ------ 51 with 3
  lesions
• At 10 years ------ 56 with 1 lesion
• At 15 years ------ 75 with 1 lesion

20 increased risk after 10 years
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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

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Brief Bibliography

• PN Shams, GT Plant. Optic Neuritis A Review
• The International MS Journal 2009 16
  8289
• Multiple Sclerosis Risk after Optic Neuritis
  Final Optic Neuritis Treatment Trial Follow-Up.
  The Optic Neuritis Study Group. Arch Neurol.
  2008 June 65(6) 727732.
• The Clinical Profile of Optic Neuritis.
  Experience of the Optic Neuritis Treatment Trial.
  Optic Neuritis Study Group. Arch Ophthalmol.
  19911091673-1678
• 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
• Long-term Brain Magnetic Resonance Imaging
  Changes After Optic Neuritis in Patients
• Without Clinically Definite Multiple
  Sclerosis Optic Neuritis Study Group. Arch
  Neurol. 2004611538-1541

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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