Ontt ppt latest new vj

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The Optic Neuritis Treatment Trial (ONTT) (1988-2006), a Multicenteric randomized trial funded by the National Eye Institute
457 patients between 18 and 46 years of age with acute unilateral optic neuritis and no indication of a causal systemic disease other than MS were enrolled.

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Ontt ppt latest new vj

  1. 1. Vijay Joshi OPTIC NEURITIS TREATMENT TRIAL (ONTT)
  2. 2. The Optic Neuritis Treatment Trial (ONTT) (1988-2006), a multicenteric randomized trial funded by the National Eye Institute 457 patients between 18 and 46 years of age with acute unilateral optic neuritis and no indication of a causal systemic disease other than MS were enrolled. 85% white population were enrolled The study protocol was approved by the Institutional Review Board at each clinical centre. Written informed consent was obtained from each patient, in adherence with the Declaration of Helsinki.
  3. 3. 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. THE OPTIC NEURITIS TREATMENT TRIAL
  4. 4. (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? QUESTIONS ASKED
  5. 5. Treatment phase ( ONTT ) Long term follow up phase ( Longitudinal optic neuritis study [LONS] )
  6. 6. The major eligibility criteria for enrolment into the ONTT included the following: Age range of 18 to 46 years Acute unilateral optic neuritis with visual symptoms for 8 days or less A relative afferent pupillary defect and a visual field defect in the affected eye No previous episodes of optic neuritis in the affected eye No previous corticosteroid treatment for optic neuritis or multiple sclerosis No systemic disease other than multiple sclerosis that might be the cause of the optic neuritis PATIENT ELIGIBILITY
  7. 7. THE ONTT: METHODS  Randomization to one of 3 groups 1. IV steroids: 250 mg methylprednisolone qid x 3 days, oral prednisone (1mg/kg) x 11 days – 151 patients 2. Oral steroids: prednisone 1mg/kg/day x 14 days – 156 patients 3. Oral placebo: 14 days – 150 patients Each regimen was followed by a short oral taper. The oral prednisone and placebo groups were double masked, whereas the intravenous methylprednisolone group was single masked.
  8. 8. 7 follow up visits during the first 6 months  Primary outcome at 6 months At one year Yearly upto 1997 2001 – 2002 2006 FOLLOW UP
  9. 9. Neurological evaluation Visual Acuity Contrast Colour Fields Vision specific quality of life questionnaire BASELINE AND FOLLOW UP TESTS
  10. 10. 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
  11. 11. 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 CLASSIFICATION OF CHANGES ON BRAIN MAGNETIC RESONANCE IMAGES
  12. 12. Eligibility criteria:  18 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 BASELINE CHARACTERISTICS
  13. 13. Baseline testing included blood tests to evaluate for syphilis and systemic lupus erythematosus, a chest x-ray to evaluate for sarcoidosis, and a brain MRI scan to evaluate for changes suggestive of multiple sclerosis. Neurologic examination MRI Glucose, Antinuclear Antibody [ANA], and Fluorescent Treponemal Antibody Absorption [FTAABS1] tests CXR MS classification by Poser’s classification
  14. 14. The criteria can yield five conclusions: 1.CDMS – Clinically definite MS. Needs two attacks and some clinical or paraclinical evidences 2.LSDMS – Laboratory supported definite MS, showing oligoclonal bands and clinical or paraclinical evidences 3.CPMS – Clinically probable MS, with less restrict combinations. 4.LSPMS – Laboratory supported probable MS. Only two attacks is enough to enter this category 5.No MS – There is no clinical evidence of having MS. POSER’S CLASSIFICATION
  15. 15. 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 CSF EVALUATION AND MRI
  16. 16. 457 patients at entry …… 300 at 15 year f.u. M: F = 22.8% : 77.2% [ 1: 3 ] Age : 31.8 +/- 6.7 years RESULTS
  17. 17. ONTT: RESULTS IV steroids  More rapid recovery but same endpoint  Protective v. placebo at 2 years, not 3Years Oral prednisone  Higher rate of new ON attacks at 1 year  Highest rate of relapse at 5 years
  18. 18. The Clinical Profile of Optic Neuritis Experience of the Optic Neuritis Treatment Trial Optic Neuritis Study Group (Arch Ophthalmol. 1991;109:1673-1678)
  19. 19. 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 VISUAL ACUITY IN ON
  20. 20. 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 THE ROLE OF STEROID
  21. 21. 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 RECURRENCE OF ON
  22. 22. OPTIC NEURITIS RECURRENCE FROM THE ONTT 35% of patients experienced recurrence in the previously affected eye or an attack in the fellow eye at 10 years Recurrence rate was double in those with CDMS Recurrence rate highest in the oral steroid group
  23. 23. 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 RISK OF MS
  24. 24. CIS – Clinically isolated event [ monocular optic neuritis ] CDMS – Clinically definite MS MRI AND RISK OF DEVELOPING MS
  25. 25. At 5 years ----- 16% At 10 years ----- 22% At 15 years ------ 25% WITHOUT MRI FINDINGS Only 3% increased risk after 10 years
  26. 26. 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 WITH MRI FINDINGS 20% increased risk after 10 years
  27. 27. Male gender Optic nerve head swelling [ papillitis ] Atypical presentation  Severe optic disc swelling  Disc or peripapillary haemorrhages  Retinal exudates  Absent pain  Vision no PL PROTECTIVE FACTORS
  28. 28. RADIOLOGIC PREDICTORS OF MS 10 YEAR ONTT DATA White matter lesions on MRI  Risk is 22% if no baseline brain lesions  Risk is 56% if ≥ 1 baseline lesion  Risk increases with increasing lesions
  29. 29. CLINICAL PREDICTORS OF MS ONTT 10 YEAR DATA Low risk if no MRI lesions and  Male gender  Optic disc swelling No CDMS in subset with above and one of  No pain  Severe disc edema  Peripapillary hemorrhages  Retinal exudates
  30. 30. 1. Oral prednisolone therapy alone is contraindicated in the treatment of acute optic neuritis, since, it did not improve visual outcome and was associated with a significant increase in the risk of new attacks of optic neuritis. 2. A patient presenting with acute optic neuritis should have brain MRI scan. If the brain shows lesions supportive of multiple sclerosis (MS), regardless of the severity of visual loss, each patient should receive immediate intravenous methylprednisolone (1 gm daily) for 3 days followed by oral prednisolone (1 mg/kg/day) for 11 days. This therapy will delay conversion to clinical MS over the next 2 years. 3. Chest x-ray, blood tests and lumbar puncture are not indicated for typical cases of optic neuritis CONCLUSION
  31. 31. 4. Indications for intravenous methylprednisolone in acute optic neuritis patients with a normal brain MRI scan are:  Visual loss in both eyes simultaneously or subsequently within hours or days of each other.  When the only good eye is affected.  When the slow progressive visual loss continues to occur.
  32. 32. 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 The primary visual outcome from treatment was assessed after 6 months. Patients continued to be followed yearly to assess visual and neurologic courses. ONTT
  33. 33. Age group < 18 years not taken. ON is frequent in children after viral ds, post vaccination Doesn’t associate other systemic ds with optic neuritis Doesn’t include atypical ON Doesn’t comment upon alternative treatment modality other than steroids LACUNAE
  34. 34. ONTT data did not answer why increased rates of ON recurrence ( a presumed indicator of demyelinating disease activity) were not associated with increased rates of MS development No other study has confirmed the increased rate of recurrence of ON in pts treated with oral corticosteroids ONTT did not explain the significance of slight benefit of intravenous treatment seen in pts with more severe vision loss Did not include a treatment arm of patients receiving high dose oral steroids, which may have proved to be similarly effective LIMITATIONS
  35. 35. Purpose To assess the beneficial and adverse effects of corticosteroid treatment for optic neuritis. To determine the natural history of vision in patients who suffer optic neuritis. To identify risk factors for the development of multiple sclerosis in patients with optic neuritis. LONGITUDINAL OPTIC NEURITIS STUDY (LONS)
  36. 36. The LONS was established as a continuation of the ONTT which was an investigator-initiated 15-center study funded by the National Eye Institute designed to evaluate the efficacy of corticosteroids in restoring vision after optic neuritis. Major eligibility criteria for enrolment included: age range 18 to 45 years inclusive, an acute clinical syndrome consistent with unilateral optic neuritis with visual symptoms of eight days or less, a relative afferent pupillary defect and a visual field defect in the affected eye, and no previous treatment for MS (if it had been diagnosed previously). The latter criterion had the effect of limiting the cohort to patients with either isolated optic neuritis or early untreated MS LONS
  37. 37. The primary aims of the LONS are to evaluate the visual course and neurologic course for a period of time longer than the six month follow up period of the ONTT The key importance of the LONS is to provide insight into the early stages of multiple sclerosis. This is a stage of the disease that is poorly studied and therefore incompletely understood. The LONS continues to provide valuable insights into this stage of the disease.
  38. 38. CHAMPS STUDY Effect of Interferon B 1a treatment in patients with optic neuritis and MRI changes compatible with MS  Significantly less CDMS  Less progression of MRI lesions
  39. 39. CHAMPS (2000) 383 pts 1st acute clinical demyelinating event (CIS), including 192 (50%) optic neuritis and MR showed > 2 lesions All received IV + oral steroids within 14 d Randomized to weekly 30 µg IM interferon beta-1a (Avonex) vs placebo within 27d Planned for 3 year treatment/followup Endpoint: clinically definite MS Study terminated after 1st interim analysis Cumulative probability for MS significantly lower in treatment than control (35% vs 50%, p = 0.002); reduction in rate by about half MR lesion volume, new/enlarging lesions, and enhancing lesions all significantly lower
  40. 40. The CHAMPS study showed that interferon beta 1-A may reduce the conversion to multiple sclerosis in high risk patients by approximately 50%. Highlights the importance of early therapy for multiple sclerosis. It states that reducing both the clinical and imaging abnormalities may produce prolonged benefit.
  41. 41. 1. 44 % reduction in risk of developing a second demyelinating event in treated group. 2. 57% reduction in development of new T2 lesion on MRI in the treated group. 3. 91% reduction in T2 lesion volume in treated group. 4. 82% of those in the placebo group developed ongoing, new lesions on MRI. RESULTS
  42. 42. (Controlled High Risk Avonex Multiple Sclerosis Prevention Surveillance) Post Rx analysis immediate vs delayed treatment in CHAMPS Trial 40% difference in conversion rate to CDMS at 10 years early vs delayed Delayed group double recurrence rate CHAMPIONS (2006)
  43. 43. An observational study conducted RP centre, 2010 to evaluate the efficacy and safety profile of intravenous dexamethasone showed that the intravenous pulse dexamethasone led to rapid recovery of vision in acute optic neuritis, without any serious side effects. Later on, a case-control study was done to compare the efficacies of intravenous mega-dose methylprednisolone and intravenous dexamethasone in terms of visual recovery, as well as to evaluate their side effects. Intravenous dexamethasone was found to be as effective as mega-dose intravenous methylprednisolone therapy recommended by the ONTT study, with the added advantage of being easier to administer and less costly (costing one sixth of injection methylprednisolone) RP CENTRE STUDY
  44. 44. The PRISMS (Prevention of Relapses and Disability by Interferon -1aβ Subcutaneously in Multiple Sclerosis) Trial assessed efficacy of interferon (IFN)- 1a in dosages of 22 µg and 44 µg s.c. given subcutaneouslyβ compared to placebo in RRMS (relapsing-remitting multiple sclerosis) patients, and it was seen that both the treatment groups had fewer relapses. PRISMS
  45. 45. The most recent study has been the Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, which included patients with a single neurologic event and at least 2 clinically silent MRI lesions. In a 24-month study period, standard dose of interferon- 1b (Betaseronβ ® , Bayer Health Care Pharmaceuticals) was seen to reduce the risk of MS by 50% BENEFIT
  46. 46. A new drug called natalizumab (Antegren) is causing excitement in the neurology community, is a molecule designed to interfere with movement of potentially damaging immune cells from the bloodstream, across the blood-brain barrier and into the brain and spinal cord.  This monoclonal antibody attaches to a protein called alpha 4-integrin on the surface of white blood cells, which serves to block such immune cell movement. LATEST IN TREATMENT OF ON
  47. 47.  The concept of an NMO spectrum disorder was unknown and NMO did not score highly on the differential diagnosis of optic neuritis.  Little consideration was given to genetic factors and to the patient’s ethnic background.  The presence of aquaporin 4 autoantibodies also influences the long-term management of a patient following optic neuritis  The discovery of the aquaporin 4 autoantibody has profoundly improved diagnostic and prognostic accuracy. It has encouraged a strong deviation away from ONTT based protocols in some cases of optic neuritis where NMO spectrum disease may be the underlying aetiology.  A further large scale study is also indicated to consider how serological markers such as GFAP and N-acetyl aspartate and genetic influences can influence the management and outcome of acute isolated optic neuritis. FUTURE
  48. 48. Thanks

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