European journal of neurology · 2025
Долгосрочные результаты и прогнозы идиопатического оптического нерита: исследование кохарта.
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Leger Benjamin, Gueguen Antoine, Lecler Augustin, Boudot de la Motte Marine, Lamirel Cédric, Bensa Caroline, Vignal Catherine, Marignier Romain, Papeix Caroline, Deschamps Romain
Аннотация
ВВЕДЕНИЕ: Пациенты, у которых был диагностирован оптический неуриит (ON), не соответствующий диагностическим критериям для множественных склерозов (MS), расстройства спектра нейромиелита оптика (NMO-SD), были подвергнуты тестированию с отрицательным mielin oligodendrocyte glycoprotein Immonglobulin G и в отношении которых было исключено системное заболевание, относятся к категории лиц, страдающих идиопатией (IDON). Это было моноцентрическое ретроспективное исследование. Критерии включения были следующими: пациенты с IDON, отсутствие альтернативного диагноза в течение первого периода 2 годы, последующие меры по крайней мере 5 Годы. Результаты: Thirty-six Включены пациенты. После медианной проверки 9 Годы, был сохранен диагноз IDON для 77.8% (n = 28) пациентов, в то время как 22.2% (n = 8) переоборудован в альтернативный диагноз после медианы 6 Годы. Four пациентов, переоборудованных в MS, two синдрома клинической изоляции и two Серонегативная NMO-SD. В числе 28 пациенты, у которых был диагностирован IDON, 42.9% (n = 12) опытный ОН, который происходит главным образом (90%) в рамках первого 5 годы болезни. Реабилитация была начата в 10 ЗАПЛАНИРОВАННЫЕ ЗАСЕДАНИЯ 12 пациентов, в том числе 6 У пациентов не было рецидивов в процессе лечения. Для 28 Пациенты, оставшиеся с IDON, конечная лучшая корректированная зрительная акустика (BCVA) была переменной. При всем уважении, 35.7% и 25.9% БКВА ниже, чем у пациентов, 0.5 и 0.2В то время как 50% извлечена окончательная ВКВА 10/10. Заключение: значительная доля когорт, прошедших альтернативную диагностику после 2 Годы, поощрение более длительного наблюдения за пациентами IDON. Лечение техобслуживания часто было эффективным в случае периодического ВС.
Оригинал публикации
Long-Term Outcome and Prognosis of Idiopathic Optic Neuritis: A Cohort Study.
INTRODUCTION: Patients diagnosed with optic neuritis (ON) who did not fulfil the diagnostic criteria for multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMO-SD), tested negative myelin oligodendrocyte glycoprotein immunoglobulin G and for which a systemic disease has been excluded are classified as having idiopathic ON (IDON).
METHODS: This was a monocentric retrospective observational study. Inclusion criteria were as follows: patients with IDON, absence of an alternative diagnosis during the first 2 years, follow-up of at least 5 years.
RESULTS: Thirty-six patients were included. After a median follow-up of 9 years, a diagnosis of IDON was retained for 77.8% (n = 28) of patients, whereas 22.2% (n = 8) converted to an alternative diagnosis after a median of 6 years. Four patients converted to MS, two to clinically isolated syndrome and two to seronegative NMO-SD. Among the 28 patients who remained diagnosed with IDON, 42.9% (n = 12) experienced recurrent ON, occurring mostly (90%) within the first 5 years of the disease. Maintenance therapy was initiated in 10 of the 12 patients, among whom 6 patients had no recurrence under treatment. For the 28 patients who remained with IDON, the final best corrected visual acuity (BCVA) was variable. Respectively, 35.7% and 25.9% of patients had a BCVA inferior to 0.5 and 0.2, whereas 50% recovered a final BCVA of 10/10.
CONCLUSION: A significant proportion of the cohort converted to an alternative diagnosis after 2 years, encouraging an extended follow-up of IDON patients. Maintenance therapies were often effective in case of recurrent ON.
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Introduction
Patients diagnosed with optic neuritis (ON) who do not meet the multiple sclerosis (MS) [ 1 ] criteria, neuromyelitis optica spectrum disorders (NMO‐SD) criteria [ 2 ] and tested negative for myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG), are classified as idiopathic ON (IDON) [ 3 ], after exclusion of systemic diseases such as neurosarcoidosis. The frequency of IDON varies depending on ethnicity, diagnostic criteria and length of follow‐up, ranging from 15% to 56% [ 4 , 5 , 6 ].
In 2018, we reported the visual outcome of 23 IDON patients (median follow‐up time, 3.2 years). In order to exclude patients with MS, our inclusion criteria for IDON were strict, with a minimal follow‐up of 2 years and at least two brain magnetic resonance imaging (MRI) showing no evidence of demyelination. We found that the visual prognosis is heterogeneous among IDON patients, with 20% of them having severe visual sequelae [ 7 ]. However, the long‐term outcome of such patients remains largely unknown. The objective of this study was to assess the diagnosis at the last follow‐up and prognosis of IDON patients with at least 5 years of follow‐up.
Methods
Patients
This was a monocentric retrospective observational study, including patients from two different cohorts. In the first cohort [ 7 ], the records of 513 patients admitted to the Department of Neurology (Fondation A. de Rothschild, Paris, France) for acute ON between December 2011 and December 2016 were consecutively reviewed, including 23 patients diagnosed with IDON. In the second cohort named OCTON, 120 patients with ON between October 2015 and July 2017 were enrolled in the same department, including 19 patients with IDON [ 8 ]. The current study was approved by our institutional Research Ethics Board and informed consent was obtained from patients.
Inclusion Criteria
Patients included fulfilled the following criteria: (1) acute ON, (2) negative reaction to aquaporine‐4 (AQP4) and MOG‐IgG, (3) at least two brain MRIs and one spinal cord MRI during the first 2 years of follow‐up, (4) no lesion suggestive of MS on MRI during the first 2 years and (5) follow‐up of at least 5 years. All patients fulfilled the 2022 diagnostic criteria for definite or possible ON [ 9 ]. AQP4 and MOG‐IgG were both tested by live cell‐based assay performed at a referral centre (Lyon Neuroscience Research Centre, Lyon, France).
Data Collection
All patients were investigated according to the hospital's routine standard exploration protocol for ON [ 7 , 8 ]. Records were reviewed to acquire demographic data (sex, age); clinical ophthalmologic findings at baseline, during the course and at the last follow‐up (best corrected visual acuity [BCVA], orbital pain, optic disk swelling); MRI characteristics at baseline and during the course (segments involved, chiasmal or retrochiasmal involvement); blood analysis (standard and additional tests, genetic testing, lumbar puncture), treatment received (plasmapheresis during the disease course, use of immunosuppressive therapy) and number and characteristics of ON relapses. Final BCVA was measured with the standard Snellen chart and converted to the logarithmic minimum angle of resolution (logMAR) for analysis [ 7 , 10 ]. Poor outcome was defined as BCVA ≤ 0.5 (i.e., logMAR ≥ 0.3) and very poor outcome as BCVA ≤ 0.2 (i.e., logMAR ≥ 0.7) [ 7 ]. The final thickness of the peri‐papillary retinal nerve fibre layer (pRNFL) and volume of the macular ganglion cell layer (mGCL) were measured with spectral domain optical coherence tomography (OCT, Spectralis, Heidelberg Engineering, Heidelberg, Germany). Layer segmentation was performed automatically using Heidelberg software.
Follow‐Up and Final Diagnosis
Final diagnosis was assessed based on clinical and imaging criteria and classified into two categories: IDON or alternative diagnosis. Alternative diagnoses were classified as MS/clinically isolated syndrome (CIS) or seronegative NMO‐SD. MS diagnosis was based on the 2017 McDonald's criteria [ 1 ]. Diagnosis of CIS was derived from these criteria, with at least one lesion suggestive of MS fulfilling dissemination in time but not dissemination in space [ 11 ]. Diagnosis of seronegative NMO‐SD was based on the international consensus for NMO‐SD [ 2 ]. Patients lost to follow‐up were reached by phone for a standardised telephone interview investigating new symptoms suggestive of ON relapse, changes in visual function, emergence of other neurological symptoms, pursuit of an immunomodulatory treatment and pursuit of outpatient follow‐up.
Statistics
Predictive factors for conversion to an alternative diagnosis were investigated by comparing the characteristics of patients with a final diagnosis of IDON with those of patients with an alternative diagnosis. Comparisons between categorical variables were performed using the Fischer exact test and comparisons between quantitative data were performed using a Mann–Whitney U . The level of significance was set as a correct p value of < 0.05. Statistical analyses were performed using Jamovi and R software.
Results
Among 42 patients with an initial diagnosis of IDON from the two cohorts, 36 fulfilled the inclusion criteria. Patients excluded had an insufficient follow‐up ( n = 1), no follow‐up MRI ( n = 4) or unknown MOG/AQP4 status ( n = 1). Median clinical follow‐up was 9 years (mean, 9.3; range, 5.1–26.2) and median radiological follow‐up was 5.8 years (mean, 5.5; range, 0.5–17.6). All ON relapses were treated with intravenous methylprednisolone (1000 mg/day for at least 3 days).
Alternative Diagnosis ( n = 8)
At the end of the follow‐up, 22.2% ( n = 8) converted to an alternative diagnosis. Six patients converted to MS ( n = 4) or CIS ( n = 2) and two patients to NMO‐SD. The median time to conversion to an alternative diagnosis was 6 years (range, 2.1–8.9).
Diagnosis of MS was made through radiological follow‐up without any clinical manifestation in two patients. NMO‐SD was diagnosed by clinical manifestation: one patient experienced recurrent myelitis, and one patient experienced a pseudo‐tumoral lesion leading to hemiparesis. No predictive factors for conversion to an alternative diagnosis were identified (Table 1 ).
TABLE 1 Patient characteristics and visual outcome in the three groups. Variables IDON (28 patients/58 ON episodes) MS/CIS (6 patients/10 ON episodes) NMO‐SD (2 patients/6 ON episodes) IDON versus alternative diagnosis ( p ) †
Follow‐up in years, median (mean, range) 8.8 (9.5;5.1–26.2) 8.7 (8.5;5.6–11.8) 10 (10; 9.6–10.5) 0.894 Sex, female, n (%) 21 (75) 4 (66.7) 2 (100) 1.000 Age at onset, median (mean, range) 33 (36.3;11–63) 27 (29.5; 21–44) 45 (44.5; 36–53) 0.361 Plasmapheresis during the course, n (%) 9 (32.1) 3 (50) 0 1.000 Initial logMAR, median (mean, range) 0.8 (1.3;0–3) a
0.4 (0.8;0–3) a
3 (2.3;0.7–3) a
0.975 Bilateral ON, n (%) 7 (25) 1 (16.7) 1 (50) 1.000 Pain, n (%) 21 (75) 5 (100) b
1 (50) 1.000 Optic disc swelling, n (%) 13 (46.4) 1 (16.7) 1 (50) 0.424 CSF pleiocytosis, n (%) 7 (29.2) c
0 c
1 (50) 0.642 Elevated CSF protein, n (%) 3 (12.5) c
0 c
0 1.000 CSF‐restricted oligoclonal bands, n (%) 10 (43.5) d
4 (80) d
0 d
0.390 (Retro)Chiasmatic involvement, n (%) 6 (23.1) e
1 (16.7) 0 1.000 Perineuritis, n (%) 5 (19.2) e
2 (33.3) 1 (50) 0.355 Recurrent ON, n (%) 12 (42.9) 3 (50) 2 (100) 0.434 Final BCVA ≤ 0.5, n (%) 10 (35.7) 2 (33.3) 0 0.691 Final BCVA ≤ 0.2, n (%) 7 (25) 1 (16.7) 0 0.651 Final BCVA ≤ 0.2 in both eyes, n (%) 2 (7.1) 0 0 1.000 Final logMar, median (mean, range) 0 (0.45;0–3) f
0 (0.54; 0–3) f
0 (0.08; 0–0.3) f
0.851 Final pRNFL (μm), median (mean, range) 54 (64.2; 27–106) g
77 (70.8; 40–103) g
67.5 (68.3; 64–74) 0.488 Final mGCL (mm 3 ), median (mean, range) 0.75 (0.80; 0.46–1.15) h
0.84 (0.79;0.46–1.15) h
0.77 (0.77; 0.66–0.88) 0.816
Note: Initial logMAR values a for 44, 9 and 3 eyes in the IDON, MS/CIS and NMO‐SD groups. Missing data concerning pain b for 1 MS/CIS patient concerning pain. Missing data for CSF analysis c in four IDON patients and one MS/CIS patient. Missing data for CSF‐restricted oligoclonal bands d in five IDON patients, one MS/CIS patient and one NMO‐SD patient. Missing optic nerve MRI data e for two patients in IDON group. Final logMAR values f for 44, 9 and 4 eyes in the IDON, MS/CIS and NMO‐SD groups calculated over all eyes with a history of ON. pRNFL and mGCL data were calculated over all eyes with a history of optic neuritis. pRNFL data were missing g for, respectively, four IDON and one MS/CIS patient and GCL data were missing h for, respectively, five IDON and one MS/CIS patients. Abbreviations: BCVA, best corrected visual acuity; CIS, clinically isolated syndrome; CSF, cerebro‐spinal fluid; IDON, idiopathic optic neuritis; logMAR, logarithmic minimum angle of resolution; mGCL, macular ganglion cell layer; MS, multiple sclerosis; NMO‐SD, neuromyelitis optica spectrum disorder; ON, optic neuritis; pRNFL, peripapillary retinal nerve fibre. † Alternative diagnosis (MS/CIS and NMO‐SD) characteristics compared to IDON characteristics.
Patient characteristics and visual outcome in the three groups.
Note: Initial logMAR values a for 44, 9 and 3 eyes in the IDON, MS/CIS and NMO‐SD groups. Missing data concerning pain b for 1 MS/CIS patient concerning pain. Missing data for CSF analysis c in four IDON patients and one MS/CIS patient. Missing data for CSF‐restricted oligoclonal bands d in five IDON patients, one MS/CIS patient and one NMO‐SD patient. Missing optic nerve MRI data e for two patients in IDON group. Final logMAR values f for 44, 9 and 4 eyes in the IDON, MS/CIS and NMO‐SD groups calculated over all eyes with a history of ON. pRNFL and mGCL data were calculated over all eyes with a history of optic neuritis. pRNFL data were missing g for, respectively, four IDON and one MS/CIS patient and GCL data were missing h for, respectively, five IDON and one MS/CIS patients.
Abbreviations: BCVA, best corrected visual acuity; CIS, clinically isolated syndrome; CSF, cerebro‐spinal fluid; IDON, idiopathic optic neuritis; logMAR, logarithmic minimum angle of resolution; mGCL, macular ganglion cell layer; MS, multiple sclerosis; NMO‐SD, neuromyelitis optica spectrum disorder; ON, optic neuritis; pRNFL, peripapillary retinal nerve fibre.
Alternative diagnosis (MS/CIS and NMO‐SD) characteristics compared to IDON characteristics.
IDON Patients ( n = 28)
Among the 28 patients who remained classified as IDON patients, 25% ( n = 7) of patients experienced at least one episode of bilateral ON, and 46.4% ( n = 13) experienced optic disc swelling during an episode of ON across the disease course (Table 1 ). Of the 28 IDON patients, 42.9% ( n = 12) experienced recurrent ON, mainly unilateral (96.7%), with an average number of recurrences per patient of 2.5 (1–5). Approximately, 91.2% of them were women ( n = 11). Recurrences occurred in 90% of cases within the first 5 years of the disease (Figure 1 ). Median time between the first episode and the first recurrence was 8.5 months (mean, 16.8; range, 2–51) and median time between the first and last recurrence registered was 3.8 years (mean, 4.1; range 0.2–15.9).
Optic neuritis recurrences in idiopathic optic neuritis patients and impact of treatment on disease course.
Maintenance therapy was initiated in 10 of 28 IDON patients (35.7%), only in those with recurrent ON. Treatment used were azathioprine ( n = 7), mycophenolate mofetil ( n = 7) and rituximab ( n = 3), which was used as a second‐line treatment in every case. Among the 10 patients, four had a recurrence under an immunosuppressive treatment for a total of six recurrences, including two patients having early relapses during the initiation of azathioprine therapy (Figure 1 ).
The median ophthalmological follow‐up time was 8.2 years (mean, 8.4; range, 4.5–15.8). Final BCVA was poor in 35.7% ( n = 10) and very poor in 25% ( n = 7). Two patients (7.1%) had a very poor visual outcome in both eyes. The median final BCVA was 1 (i.e., logMAR 0). The median OCT follow‐up time was 4.8 years (mean, 4.8; range, 0.5–15.6). Final OCT values for pRNFL and mGCL are described in Table 1 . No significant correlation was observed between the number of recurrences and final visual acuity or OCT outcomes.
Discussion
Since the ONTT and the identification of AQP4 and MOG antibodies [ 4 , 12 , 13 ], this study has one of the longest follow‐up durations of IDON. First, we found that approximately one‐quarter of patients with initially strict inclusion criteria for IDON, converted to an alternative diagnosis during this follow‐up period. The median time to conversion was 6 years, which supports a long‐term follow‐up strategy for these patients. Second, among patients who retained a diagnosis of IDON, we confirm that 25% had an overall poor visual outcome. This is consistent with recent studies [ 12 , 14 ]. At the same time, it should be noted that in our cohort, as in the study of Hassan et al., half of IDON patients recovered full normal VA. These results highlight the heterogeneity of these IDONs and their underlying causes. Third, we found that nearly half of the IDON patients experienced ON relapses, sometimes frequently, with a mean of 2.5 relapses per patient. These relapses mainly occurred within the first 5 years. Finally, and importantly, we observed that initiating maintenance immunosuppressive therapy in patients with a relapsing form of IDON may reduce the risk of recurrence, even though multicentric controlled studies are obviously needed to confirm this result.
One limitation of our study was the lack of systematic radiological follow‐up, which could have led to an underestimation of MS diagnosis, though such follow‐up may not always be feasible in routine clinical practice. With longer follow‐up, it is possible some of the idiopathic patients could have converted to MS. Moreover, we could not rule out a selection bias, with the inclusion of particularly severe patients, due to the retrospective nature of the study and the recruitment in a tertiary centre.
In conclusion, in this cohort of IDON patients with a long‐term follow‐up, a significant proportion converted to an alternative diagnosis, which argues for a longer follow‐up. Visual outcome can be poor in patients with IDON, and the risk of recurrence is high. However, immunosuppressive treatments have shown to be effective in cases of recurrence, but this requires confirmation.
Author Contributions
Benjamin Leger: writing – original draft, investigation, conceptualization, formal analysis, visualization, methodology, data curation, validation. Antoine Gueguen: writing – review and editing. Augustin Lecler: writing – review and editing. Marine Boudot de la Motte: writing – review and editing. Cédric Lamirel: writing – review and editing. Caroline Bensa: writing – review and editing. Catherine Vignal: writing – review and editing. Romain Marignier: writing – review and editing. Caroline Papeix: writing – review and editing, resources. Romain Deschamps: conceptualization, methodology, supervision, writing – review and editing, investigation, resources, project administration, validation.
Conflicts of Interest
The authors declare no conflicts of interest.
Patients diagnosed with optic neuritis (ON) who do not meet the multiple sclerosis (MS) [ 1 ] criteria, neuromyelitis optica spectrum disorders (NMO‐SD) criteria [ 2 ] and tested negative for myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG), are classified as idiopathic ON (IDON) [ 3 ], after exclusion of systemic diseases such as neurosarcoidosis. The frequency of IDON varies depending on ethnicity, diagnostic criteria and length of follow‐up, ranging from 15% to 56% [ 4 , 5 , 6 ].
In 2018, we reported the visual outcome of 23 IDON patients (median follow‐up time, 3.2 years). In order to exclude patients with MS, our inclusion criteria for IDON were strict, with a minimal follow‐up of 2 years and at least two brain magnetic resonance imaging (MRI) showing no evidence of demyelination. We found that the visual prognosis is heterogeneous among IDON patients, with 20% of them having severe visual sequelae [ 7 ]. However, the long‐term outcome of such patients remains largely unknown. The objective of this study was to assess the diagnosis at the last follow‐up and prognosis of IDON patients with at least 5 years of follow‐up.
Methods
Patients
This was a monocentric retrospective observational study, including patients from two different cohorts. In the first cohort [ 7 ], the records of 513 patients admitted to the Department of Neurology (Fondation A. de Rothschild, Paris, France) for acute ON between December 2011 and December 2016 were consecutively reviewed, including 23 patients diagnosed with IDON. In the second cohort named OCTON, 120 patients with ON between October 2015 and July 2017 were enrolled in the same department, including 19 patients with IDON [ 8 ]. The current study was approved by our institutional Research Ethics Board and informed consent was obtained from patients.
Inclusion Criteria
Patients included fulfilled the following criteria: (1) acute ON, (2) negative reaction to aquaporine‐4 (AQP4) and MOG‐IgG, (3) at least two brain MRIs and one spinal cord MRI during the first 2 years of follow‐up, (4) no lesion suggestive of MS on MRI during the first 2 years and (5) follow‐up of at least 5 years. All patients fulfilled the 2022 diagnostic criteria for definite or possible ON [ 9 ]. AQP4 and MOG‐IgG were both tested by live cell‐based assay performed at a referral centre (Lyon Neuroscience Research Centre, Lyon, France).
Data Collection
All patients were investigated according to the hospital's routine standard exploration protocol for ON [ 7 , 8 ]. Records were reviewed to acquire demographic data (sex, age); clinical ophthalmologic findings at baseline, during the course and at the last follow‐up (best corrected visual acuity [BCVA], orbital pain, optic disk swelling); MRI characteristics at baseline and during the course (segments involved, chiasmal or retrochiasmal involvement); blood analysis (standard and additional tests, genetic testing, lumbar puncture), treatment received (plasmapheresis during the disease course, use of immunosuppressive therapy) and number and characteristics of ON relapses. Final BCVA was measured with the standard Snellen chart and converted to the logarithmic minimum angle of resolution (logMAR) for analysis [ 7 , 10 ]. Poor outcome was defined as BCVA ≤ 0.5 (i.e., logMAR ≥ 0.3) and very poor outcome as BCVA ≤ 0.2 (i.e., logMAR ≥ 0.7) [ 7 ]. The final thickness of the peri‐papillary retinal nerve fibre layer (pRNFL) and volume of the macular ganglion cell layer (mGCL) were measured with spectral domain optical coherence tomography (OCT, Spectralis, Heidelberg Engineering, Heidelberg, Germany). Layer segmentation was performed automatically using Heidelberg software.
Follow‐Up and Final Diagnosis
Final diagnosis was assessed based on clinical and imaging criteria and classified into two categories: IDON or alternative diagnosis. Alternative diagnoses were classified as MS/clinically isolated syndrome (CIS) or seronegative NMO‐SD. MS diagnosis was based on the 2017 McDonald's criteria [ 1 ]. Diagnosis of CIS was derived from these criteria, with at least one lesion suggestive of MS fulfilling dissemination in time but not dissemination in space [ 11 ]. Diagnosis of seronegative NMO‐SD was based on the international consensus for NMO‐SD [ 2 ]. Patients lost to follow‐up were reached by phone for a standardised telephone interview investigating new symptoms suggestive of ON relapse, changes in visual function, emergence of other neurological symptoms, pursuit of an immunomodulatory treatment and pursuit of outpatient follow‐up.
Statistics
Predictive factors for conversion to an alternative diagnosis were investigated by comparing the characteristics of patients with a final diagnosis of IDON with those of patients with an alternative diagnosis. Comparisons between categorical variables were performed using the Fischer exact test and comparisons between quantitative data were performed using a Mann–Whitney U . The level of significance was set as a correct p value of < 0.05. Statistical analyses were performed using Jamovi and R software.
Results
Among 42 patients with an initial diagnosis of IDON from the two cohorts, 36 fulfilled the inclusion criteria. Patients excluded had an insufficient follow‐up ( n = 1), no follow‐up MRI ( n = 4) or unknown MOG/AQP4 status ( n = 1). Median clinical follow‐up was 9 years (mean, 9.3; range, 5.1–26.2) and median radiological follow‐up was 5.8 years (mean, 5.5; range, 0.5–17.6). All ON relapses were treated with intravenous methylprednisolone (1000 mg/day for at least 3 days).
Alternative Diagnosis ( n = 8)
At the end of the follow‐up, 22.2% ( n = 8) converted to an alternative diagnosis. Six patients converted to MS ( n = 4) or CIS ( n = 2) and two patients to NMO‐SD. The median time to conversion to an alternative diagnosis was 6 years (range, 2.1–8.9).
Diagnosis of MS was made through radiological follow‐up without any clinical manifestation in two patients. NMO‐SD was diagnosed by clinical manifestation: one patient experienced recurrent myelitis, and one patient experienced a pseudo‐tumoral lesion leading to hemiparesis. No predictive factors for conversion to an alternative diagnosis were identified (Table 1 ).
TABLE 1 Patient characteristics and visual outcome in the three groups. Variables IDON (28 patients/58 ON episodes) MS/CIS (6 patients/10 ON episodes) NMO‐SD (2 patients/6 ON episodes) IDON versus alternative diagnosis ( p ) †
Follow‐up in years, median (mean, range) 8.8 (9.5;5.1–26.2) 8.7 (8.5;5.6–11.8) 10 (10; 9.6–10.5) 0.894 Sex, female, n (%) 21 (75) 4 (66.7) 2 (100) 1.000 Age at onset, median (mean, range) 33 (36.3;11–63) 27 (29.5; 21–44) 45 (44.5; 36–53) 0.361 Plasmapheresis during the course, n (%) 9 (32.1) 3 (50) 0 1.000 Initial logMAR, median (mean, range) 0.8 (1.3;0–3) a
0.4 (0.8;0–3) a
3 (2.3;0.7–3) a
0.975 Bilateral ON, n (%) 7 (25) 1 (16.7) 1 (50) 1.000 Pain, n (%) 21 (75) 5 (100) b
1 (50) 1.000 Optic disc swelling, n (%) 13 (46.4) 1 (16.7) 1 (50) 0.424 CSF pleiocytosis, n (%) 7 (29.2) c
0 c
1 (50) 0.642 Elevated CSF protein, n (%) 3 (12.5) c
0 c
0 1.000 CSF‐restricted oligoclonal bands, n (%) 10 (43.5) d
4 (80) d
0 d
0.390 (Retro)Chiasmatic involvement, n (%) 6 (23.1) e
1 (16.7) 0 1.000 Perineuritis, n (%) 5 (19.2) e
2 (33.3) 1 (50) 0.355 Recurrent ON, n (%) 12 (42.9) 3 (50) 2 (100) 0.434 Final BCVA ≤ 0.5, n (%) 10 (35.7) 2 (33.3) 0 0.691 Final BCVA ≤ 0.2, n (%) 7 (25) 1 (16.7) 0 0.651 Final BCVA ≤ 0.2 in both eyes, n (%) 2 (7.1) 0 0 1.000 Final logMar, median (mean, range) 0 (0.45;0–3) f
0 (0.54; 0–3) f
0 (0.08; 0–0.3) f
0.851 Final pRNFL (μm), median (mean, range) 54 (64.2; 27–106) g
77 (70.8; 40–103) g
67.5 (68.3; 64–74) 0.488 Final mGCL (mm 3 ), median (mean, range) 0.75 (0.80; 0.46–1.15) h
0.84 (0.79;0.46–1.15) h
0.77 (0.77; 0.66–0.88) 0.816
Note: Initial logMAR values a for 44, 9 and 3 eyes in the IDON, MS/CIS and NMO‐SD groups. Missing data concerning pain b for 1 MS/CIS patient concerning pain. Missing data for CSF analysis c in four IDON patients and one MS/CIS patient. Missing data for CSF‐restricted oligoclonal bands d in five IDON patients, one MS/CIS patient and one NMO‐SD patient. Missing optic nerve MRI data e for two patients in IDON group. Final logMAR values f for 44, 9 and 4 eyes in the IDON, MS/CIS and NMO‐SD groups calculated over all eyes with a history of ON. pRNFL and mGCL data were calculated over all eyes with a history of optic neuritis. pRNFL data were missing g for, respectively, four IDON and one MS/CIS patient and GCL data were missing h for, respectively, five IDON and one MS/CIS patients. Abbreviations: BCVA, best corrected visual acuity; CIS, clinically isolated syndrome; CSF, cerebro‐spinal fluid; IDON, idiopathic optic neuritis; logMAR, logarithmic minimum angle of resolution; mGCL, macular ganglion cell layer; MS, multiple sclerosis; NMO‐SD, neuromyelitis optica spectrum disorder; ON, optic neuritis; pRNFL, peripapillary retinal nerve fibre. † Alternative diagnosis (MS/CIS and NMO‐SD) characteristics compared to IDON characteristics.
Patient characteristics and visual outcome in the three groups.
Note: Initial logMAR values a for 44, 9 and 3 eyes in the IDON, MS/CIS and NMO‐SD groups. Missing data concerning pain b for 1 MS/CIS patient concerning pain. Missing data for CSF analysis c in four IDON patients and one MS/CIS patient. Missing data for CSF‐restricted oligoclonal bands d in five IDON patients, one MS/CIS patient and one NMO‐SD patient. Missing optic nerve MRI data e for two patients in IDON group. Final logMAR values f for 44, 9 and 4 eyes in the IDON, MS/CIS and NMO‐SD groups calculated over all eyes with a history of ON. pRNFL and mGCL data were calculated over all eyes with a history of optic neuritis. pRNFL data were missing g for, respectively, four IDON and one MS/CIS patient and GCL data were missing h for, respectively, five IDON and one MS/CIS patients.
Abbreviations: BCVA, best corrected visual acuity; CIS, clinically isolated syndrome; CSF, cerebro‐spinal fluid; IDON, idiopathic optic neuritis; logMAR, logarithmic minimum angle of resolution; mGCL, macular ganglion cell layer; MS, multiple sclerosis; NMO‐SD, neuromyelitis optica spectrum disorder; ON, optic neuritis; pRNFL, peripapillary retinal nerve fibre.
Alternative diagnosis (MS/CIS and NMO‐SD) characteristics compared to IDON characteristics.
IDON Patients ( n = 28)
Among the 28 patients who remained classified as IDON patients, 25% ( n = 7) of patients experienced at least one episode of bilateral ON, and 46.4% ( n = 13) experienced optic disc swelling during an episode of ON across the disease course (Table 1 ). Of the 28 IDON patients, 42.9% ( n = 12) experienced recurrent ON, mainly unilateral (96.7%), with an average number of recurrences per patient of 2.5 (1–5). Approximately, 91.2% of them were women ( n = 11). Recurrences occurred in 90% of cases within the first 5 years of the disease (Figure 1 ). Median time between the first episode and the first recurrence was 8.5 months (mean, 16.8; range, 2–51) and median time between the first and last recurrence registered was 3.8 years (mean, 4.1; range 0.2–15.9).
Optic neuritis recurrences in idiopathic optic neuritis patients and impact of treatment on disease course.
Maintenance therapy was initiated in 10 of 28 IDON patients (35.7%), only in those with recurrent ON. Treatment used were azathioprine ( n = 7), mycophenolate mofetil ( n = 7) and rituximab ( n = 3), which was used as a second‐line treatment in every case. Among the 10 patients, four had a recurrence under an immunosuppressive treatment for a total of six recurrences, including two patients having early relapses during the initiation of azathioprine therapy (Figure 1 ).
The median ophthalmological follow‐up time was 8.2 years (mean, 8.4; range, 4.5–15.8). Final BCVA was poor in 35.7% ( n = 10) and very poor in 25% ( n = 7). Two patients (7.1%) had a very poor visual outcome in both eyes. The median final BCVA was 1 (i.e., logMAR 0). The median OCT follow‐up time was 4.8 years (mean, 4.8; range, 0.5–15.6). Final OCT values for pRNFL and mGCL are described in Table 1 . No significant correlation was observed between the number of recurrences and final visual acuity or OCT outcomes.
Discussion
Since the ONTT and the identification of AQP4 and MOG antibodies [ 4 , 12 , 13 ], this study has one of the longest follow‐up durations of IDON. First, we found that approximately one‐quarter of patients with initially strict inclusion criteria for IDON, converted to an alternative diagnosis during this follow‐up period. The median time to conversion was 6 years, which supports a long‐term follow‐up strategy for these patients. Second, among patients who retained a diagnosis of IDON, we confirm that 25% had an overall poor visual outcome. This is consistent with recent studies [ 12 , 14 ]. At the same time, it should be noted that in our cohort, as in the study of Hassan et al., half of IDON patients recovered full normal VA. These results highlight the heterogeneity of these IDONs and their underlying causes. Third, we found that nearly half of the IDON patients experienced ON relapses, sometimes frequently, with a mean of 2.5 relapses per patient. These relapses mainly occurred within the first 5 years. Finally, and importantly, we observed that initiating maintenance immunosuppressive therapy in patients with a relapsing form of IDON may reduce the risk of recurrence, even though multicentric controlled studies are obviously needed to confirm this result.
One limitation of our study was the lack of systematic radiological follow‐up, which could have led to an underestimation of MS diagnosis, though such follow‐up may not always be feasible in routine clinical practice. With longer follow‐up, it is possible some of the idiopathic patients could have converted to MS. Moreover, we could not rule out a selection bias, with the inclusion of particularly severe patients, due to the retrospective nature of the study and the recruitment in a tertiary centre.
In conclusion, in this cohort of IDON patients with a long‐term follow‐up, a significant proportion converted to an alternative diagnosis, which argues for a longer follow‐up. Visual outcome can be poor in patients with IDON, and the risk of recurrence is high. However, immunosuppressive treatments have shown to be effective in cases of recurrence, but this requires confirmation.
Author Contributions
Benjamin Leger: writing – original draft, investigation, conceptualization, formal analysis, visualization, methodology, data curation, validation. Antoine Gueguen: writing – review and editing. Augustin Lecler: writing – review and editing. Marine Boudot de la Motte: writing – review and editing. Cédric Lamirel: writing – review and editing. Caroline Bensa: writing – review and editing. Catherine Vignal: writing – review and editing. Romain Marignier: writing – review and editing. Caroline Papeix: writing – review and editing, resources. Romain Deschamps: conceptualization, methodology, supervision, writing – review and editing, investigation, resources, project administration, validation.
Conflicts of Interest
The authors declare no conflicts of interest.