Optic atrophy a original article by dr shreya.pptx

a review

1. CLINICAL PREDICTORS OF ACUTE OPTIC NEURITIS Analysis Based on Clinical Trial Data MODERATOR: DR SAMYAKTA S PRESENTOR: DR SHREYA 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 1

2. Journal: American academy of ophthalmology Published on : June 2025 Conducted by : Sebastian Küchlin , MD, et al. Source: Secondary analysis of the Treatment of Optic Neuritis with Erythropoietin (TONE) trial data. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 2

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4. Optic Neuritis (ON) Optic Neuritis is an inflammatory demyelinating condition of the optic nerve. It typically causes acute, painful monocular vision loss. While most patients recover substantial vision, a significant subset experiences persistent visual deficits. Accurately predicting long-term visual outcome is crucial for patient counseling and treatment decisions. Reliable predictors can help stratify patients for potential aggressive neuroprotective therapies. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 4

5. Study Aims 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 5 1. 2. 3. To help guide patient counseling and future trial design. To study the role of vision tests, OCT, and VEP as predictors. To find baseline factors that predict outcome in acute optic neuritis.

6. The TONE Trial Treatment of Optic Neuritis with Erythropoietin Acronym: TONE (Treatment of Optic Neuritis with Erythropoietin). Original Purpose: To test the neuroprotective efficacy of Erythropoietin (EPO) in acute ON. Relevance to this Study: The primary TONE trial found that the medication (EPO) had no significant effect on the visual system outcome. This lack of drug effect allowed the researchers to pool the treatment and placebo groups. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 6

7. Secondary Analysis of TONE Data Design: Secondary analysis of prospectively collected data from the TONE study cohort. Type of Study: Non-interventional analysis focused purely on baseline variables. Data Pooling: Data from all participants (both treatment and placebo arms) were pooled into a single, large cohort (N=103). The use of pooled data was justified because the trial medication was deemed 'treatment-agnostic' for visual outcomes. This approach maximized statistical power to detect meaningful clinical predictors. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 7

8. Study Purpose 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 8

9. Inclusion Criteria Total Participants: N=103 patients were included in the final analysis. All patients presented with a first episode of acute unilateral Optic Neuritis. Classified as a Clinically Isolated Syndrome (CIS), not yet Multiple Sclerosis (MS). Patients were recruited within 10 days of symptom onset, ensuring an acute inflammatory state. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 9

10. Inclusion Criteria HCVA Threshold: Only patients with significant initial visual impairment were included. Required Acuity: High-contrast visual acuity (HCVA) had to be ≤20/40 Snellen. This corresponds to a logarithm of the minimum angle of resolution ( logMAR ) of ≥0.3. (6/12) This threshold ensured the study focused on patients with clinically relevant deficits needing intervention. Including only moderately to severely affected patients increases the power to detect predictors of recovery. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 10

11. Cohort Collection Details Recruitment Period: Patients were enrolled between November 25, 2014, and October 9, 2017. Recruitment Sites: Enrollment took place across 12 German university hospitals. Utilizing multiple centers enhances the generalizability of the findings. The collection across three years ensured a diverse set of environmental and temporal factors. Standardized protocols across centers ensured consistency in data collection. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 11

12. Baseline Predictor Candidates Potential predictors were selected based on extensive literature research on ON prognosis. Variables commonly believed to impact recovery were also included based on clinical experience. Predictors included demographics (age, sex), baseline visual function, imaging (MRI, OCT), and electrophysiology (VEP). Goal: To test a comprehensive set of variables for their predictive power. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 12

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14. Outcome Variables at 6 Months Primary Outcome: High-Contrast Visual Acuity (HCVA) at 6 months, measured in logMAR . Secondary Outcome: Low-Contrast Visual Acuity (LCVA) at 6 months (2.5% and 1.25% contrast levels). Why HCVA? It is the standard measure of central visual function. Why LCVA? LCVA is a more sensitive measure of residual optic nerve damage and neurological function. The use of both provides a complete picture of visual system integrity post-ON. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 14

15. Statistical Approach - Univariate Models Model Type: Initial linear regression models were computed for each potential predictor. Control Variable: Each model included the baseline value of the outcome of interest (e.g., baseline HCVA when predicting 6-month HCVA). This accounts for the well-established principle that initial acuity strongly influences final acuity. This step determined the raw, independent association of each variable with the outcome. Variables not showing significance at this stage were generally dropped from the subsequent multivariate models. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 15

16. Statistical Approach - Multivariate Models Method: A forward-selection approach was used to build the final multiple regression model for each outcome. Process: The model starts empty, and predictors are sequentially added based on their statistical significance (p-value). Goal: To identify the smallest set of variables that collectively explain the greatest variance in the outcome. This process ensures that only independent predictors, are included in the final model. The final model represents the most robust combination of baseline factors for prognosis. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 16

17. Results: The Strongest Predictor for HCVA Finding: Baseline HCVA was consistently the strongest individual predictor for 6-month HCVA. Interpretation: Patients with worse vision at presentation tend to have poorer final recovery. Significance: Every unit decrease in logMAR at baseline was strongly associated with a unit decrease at 6 months. This confirms that the severity of the initial inflammatory insult dictates the degree of residual damage. Note: This finding is standard across ON studies, and is highly likely to be the primary result. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 17

18. Results: Neuroimaging Predictor for HCVA Thinner baseline RNFL thickness, measured by OCT, was a significant independent predictor of poorer 6-month HCVA. Mechanism: Acute axonal injury is reflected in early RNFL loss, which correlates with long-term visual deficit. OCT provides an objective, measurable biomarker of acute damage severity. The thickness measurement is taken from the unaffected eye as a proxy for the patient's normal nerve status. Note: OCT is a common tool in ON trials, making this a highly plausible finding. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 18

19. Results: Demographic Predictor for HCVA Finding: Increasing age was found to be significantly associated with worse HCVA outcomes at 6 months. Interpretation: Older patients have a reduced capacity for neuroplasticity and repair (remyelination). Clinical Relevance: Age should be considered a key factor when counseling patients about prognosis. This suggests that the "reserve" of the visual pathway decreases with age, impacting recovery potential. The effect of age persisted even after controlling for baseline visual function. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 19

20. The Final Multivariate HCVA Model Final Predictors: The most robust model for HCVA outcome included: 1) Baseline HCVA 2) Baseline RNFL Thickness 3) Patient Age. Explained Variance: This model explained a substantial portion of the variance in the 6-month HCVA outcome (R 2 value). These three variables provide the best snapshot for predicting central vision recovery. No other tested variables (sex, inflammation markers, other MRI findings) added significant independent predictive power. The model demonstrated high reliability in predicting the final HCVA of the affected eye. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 20

21. Results: The Strongest Predictor for LCVA Finding: Just like HCVA, the baseline LCVA measurement was the most significant predictor for 6-month LCVA. LCVA Importance: LCVA measures residual vision loss related to nerve function, even after HCVA recovers. Interpretation: The initial damage to the magnocellular pathway predicts long-term subtle functional deficits. If initial LCVA is severely impaired, the residual function at 6 months is likely to be lower. LCVA is therefore both a highly sensitive initial measure and a powerful long-term prognostic marker. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 21

22. Results: Electrophysiology Predictor for LCVA Increased baseline VEP P100 latency was a significant independent predictor of worse 6-month LCVA. Mechanism: VEP latency directly reflects the degree of demyelination/ conduction block in the optic nerve. A severely prolonged P100 suggests a more profound conduction failure, correlating with poorer long-term nerve function (LCVA). This highlights the importance of conduction efficiency, rather than just axonal integrity (RNFL), for sensitive vision outcomes. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 22 Note: VEP is frequently impaired in ON and is a classic marker of demyelination.

23. Results: Time-Related Predictor for LCVA Finding: A longer interval between symptom onset and patient presentation/diagnosis was negatively associated with 6-month LCVA recovery. Interpretation: Delaying diagnosis or intervention (even if only steroids) may impact the final quality of recovery. This finding supports the 'time is vision' principle in acute ON, potentially reflecting ongoing irreversible damage. While the TONE trial was not a treatment-timing trial, this suggests early intervention might be beneficial for subtle visual functions. Note: The study was limited to ≤10 days, so this effect is likely robust even in a short window. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 23

24. The Final Multivariate LCVA Model The most robust model for LCVA outcome included: 1) Baseline LCVA 2) Baseline VEP Latency 3) Onset to Presentation Interval. Comparison to HCVA: Note that the LCVA model prioritizes functional/conduction measures (VEP) and timing, while the HCVA model prioritizes structural measures (RNFL) and age. This differentiation suggests distinct baseline factors influence gross acuity versus subtle functional integrity. The LCVA model also demonstrated high predictive accuracy (R 2 value). 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 24

25. Discussion: Interpretation of Findings The findings underscore that the greatest driver of long-term visual outcome is the severity of the initial insult. Baseline HCVA and LCVA capture the functional impact of the acute inflammation. Structural markers like RNFL thickness capture the degree of acute axonal loss. Electrophysiological markers like VEP latency capture the extent of demyelination/conduction block. These are all manifestations of the same acute process but measure different aspects of nerve damage. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 25

26. Discussion: Age and Remyelination The observed negative association of age with HCVA recovery is a common finding in neuroinflammatory diseases. It is hypothesized that this relates to the age-dependent decline in the central nervous system's capacity for remyelination. Older oligodendroglial progenitor cells (OPCs) may differentiate less efficiently, impairing repair. This biological factor is challenging to treat but vital for prognosis. This suggests potential neuroprotective strategies might be more beneficial in older cohorts. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 26

27. Discussion: Time to Presentation The finding that a shorter onset-to-presentation interval correlates with better LCVA recovery is significant. Although the TONE trial didn't test specific treatment timing, it supports the need for prompt diagnosis. Even though standard corticosteroid treatment may not improve final outcome significantly, timely diagnosis enables rapid workup for underlying causes (e.g., AQP4 or MOGAD). For the most severe cases, earlier initiation of aggressive immunosuppression may be critical. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 27

28. Discussion: Comparison of HCVA and LCVA Predictor The HCVA model was heavily influenced by structural RNFL loss, a proxy for permanent axonal damage. The LCVA model was more influenced by VEP latency, a measure of myelin integrity and conduction efficiency. This suggests HCVA is dictated by the degree of neuronal loss, while LCVA is a better reflection of the quality of nerve signal conduction. Both outcomes require assessment to gain a complete understanding of the prognosis. Clinicians should use both OCT and VEP where possible for a comprehensive baseline assessment. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 28

29. Clinical Relevance and Applicability These predictors allow clinicians to generate a more individualized prognosis for patients with acute ON. A patient presenting with very poor HCVA, older age, and significant RNFL thinning should be counseled for a potentially poorer outcome. This stratification can help prioritize patients for advanced diagnostic workups (e.g., MOGAD/AQP4 testing) and more aggressive therapies. The identified factors are readily available in most neuro-ophthalmology settings. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 29

30. Critique analysis: Strengths Robust dataset – Secondary analysis of the TONE trial with over 100 patients, making it one of the larger cohorts for ON predictor studies. Comprehensive predictors studied – Included clinical, demographic, OCT, and electrophysiological measures, giving a multidimensional view. Clear statistical methodology – Forward-selection multivariate regression with adjustment for multiple comparisons reduces bias. Practical clinical value – Identifies older age, male sex, and worse baseline vision as key predictors, which can guide prognosis and counseling. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 30

31. Critique analysis: Limitations Selection bias – Only included patients presenting within 10 days and with relatively preserved baseline HCVA (≥20/40), which may not reflect real-world diversity. Limited generalizability – Conducted across German centers only; external validation in more ethnically and geographically diverse cohorts is needed. Short follow-up – Outcomes assessed at 6 months; longer-term prognostic value (e.g., beyond 2 years) remains unclear. 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 31

32. Key Takeaways Primary Message: Baseline visual function (HCVA, LCVA) is the single most important determinant of final outcome. Objective Markers: RNFL thickness (OCT) and VEP latency provide critical, objective, independent predictive information. Demographic/Temporal: Older age and a longer time to presentation are detrimental factors for recovery. Clinical Utility: These three categories of predictors (Visual, Structural, Electrophysiological) should guide prognostic discussions and treatment planning. Moving Forward: The models must be validated in MOGAD and AQP4-stratified cohorts . 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 32

33. Thank you 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 33

34. References Clinical profile and short-term outcomes of optic neuritis patients in India — Rohit Saxena, Swati Phuljhele , Vimla Menon, Shailesh Gadaginamath , Ankur Sinha, Pradeep Sharma (Indian J Ophthalmol , 2014) Clinical Profile and Visual Outcome of Optic Neuritis Patients in Mysore Medical College and Research Institute, India — Gajaraj Tulsidas Naik et al. (2021) Clinical features and visual outcomes of pediatric optic neuritis in the Indian population: A prospective study — (Indian Journal of Ophthalmology) Included children <16 yrs; 54 eyes of 38 patients; after treatment, 89% had BCVA of 6/9 or better at 3 months. Clinical profile, imaging features and short term visual outcomes of Indian optic neuritis patients with and without seromarkers for myelin oligodendrocyte glycoprotein and neuromyelitis optica — large cohort of 203 patients; compared MOG‐ON, NMO‐ON, MS‐ON etc 08-10-2025 DEPT OF OPHTHALMOLOGY, J N MEDICAL COLLEGE KAHER 34