Search

Publisher Copyright: © 2022 Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10–13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95–100% and 83–100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.

Purpose: To evaluate presenting features, tumor size, and treatment methods for risk of metastatic death due to advanced intraocular retinoblastoma (RB). Design: International, multicenter, registry-based retrospective case series. Participants: A total of 1841 patients with advanced RB. Methods: Advanced RB was defined by 8th edition American Joint Committee on Cancer (AJCC) categories cT2 and cT3 and new AJCC-Ophthalmic Oncology Task Force (OOTF) Size Groups (1: < 50% of globe volume, 2: > 50% but < 2/3, 3: > 2/3, and 4: diffuse infiltrating RB). Treatments were primary enucleation, systemic chemotherapy with secondary enucleation, and systemic chemotherapy with eye salvage. Main Outcome Measures: Metastatic death. Results: The 5-year Kaplan-Meier cumulative survival estimates by patient-level AJCC clinical subcategories were 98% for cT2a, 96% for cT2b, 88% for cT3a, 95% for cT3b, 92% for cT3c, 84% for cT3d, and 75% for cT3e RB. Survival estimates by treatment modality were 96% for primary enucleation, 89% for systemic chemotherapy and secondary enucleation, and 90% for systemic chemotherapy with eye salvage. Risk of metastatic mortality increased with increasing cT subcategory (P < 0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastatic mortality in categories cT3c (glaucoma, hazard ratio [HR], 4.9; P = 0.011), cT3d (intraocular hemorrhage, HR, 14.0; P < 0.001), and cT3e (orbital cellulitis, HR, 19.6; P < 0.001) than in category cT2a and with systemic chemotherapy with secondary enucleation (HR, 3.3; P < 0.001) and eye salvage (HR, 4.9; P < 0.001) than with primary enucleation. The 5-year Kaplan-Meier cumulative survival estimates by AJCC-OOTF Size Groups 1 to 4 were 99%, 96%, 94%, and 83%, respectively. Mortality from metastatic RB increased with increasing Size Group (P < 0.001). Cox proportional hazards regression analysis revealed that patients with Size Group 3 (HR, 10.0; P = 0.002) and 4 (HR, 41.1; P < 0.001) had a greater risk of metastatic mortality than Size Group 1. Conclusions: The AJCC-RB cT2 and cT3 subcategories and size-based AJCC-OOTF Groups 3 (> 2/3 globe volume) and 4 (diffuse infiltrating RB) provided a robust stratification of clinical risk for metastatic death in advanced intraocular RB. Primary enucleation offered the highest survival rates for patients with advanced intraocular RB. (C) 2022 by the American Academy of Ophthalmology.

Purpose: To determine the value of clinical features for advanced intraocular retinoblastoma as defined by the eighth edition of the American Joint Committee on Cancer (AJCC) cT3 category and AJCC Ophthalmic Oncology Task Force (OOTF) Size Groups to predict the high-risk pathologic features. Design: International, multicenter, registry-based retrospective case series. Participants: Eighteen ophthalmic oncology centers from 13 countries over 6 continents shared evaluations of 942 eyes enucleated as primary treatment for AJCC cT3 and, for comparison, cT2 retinoblastoma. Methods: International, multicenter, registry-based data were pooled from patients enrolled between 2001 and 2013. High-risk pathologic features were defined as AJCC categories pT3 and pT4. In addition, AJCC OOTF Size Groups were defined as follows: (1) less than half, (2) more than half but less than two thirds, (3) more than two thirds of globe volume involved, and (4) diffuse infiltrating retinoblastoma. Main Outcome Measures: Statistical risk of high-risk pathologic features corresponding to AJCC cT3 subcategories and AJCC OOTF Size Groups. Results: Of 942 retinoblastoma eyes treated by primary enucleation, 282 (30%) showed high-risk pathologic features. Both cT subcategories and AJCC OOTF Size Groups (P < 0.001 for both) were associated with high-risk pathologic features. On logistic regression analysis, cT3c (iris neovascularization with glaucoma), cT3d (intraocular hemorrhage), and cT3e (aseptic orbital cellulitis) were predictive factors for high-risk pathologic features when compared with cT2a with an odds ratio of 2.3 (P = 0.002), 2.5 (P = 0.002), and 3.3 (P = 0.019), respectively. Size Group 3 (more than two-thirds globe volume) and 4 (diffuse infiltrative retinoblastoma) were the best predictive factors with an odds ratio of 3.3 and 4.1 (P < 0.001 for both), respectively, for high-risk pathologic features when compared with Size Groups 1 (i.e., < 50% of globe volume). Conclusions: The AJCC retinoblastoma staging clinical cT3c-e subcategories (glaucoma, intraocular hemorrhage, and aseptic orbital cellulitis, respectively) as well as the AJCC OOTF Size Groups 3 (tumor more than two thirds of globe volume) and 4 (diffuse infiltrative retinoblastoma) both allowed stratification of clinical risk factors that can be used to predict the presence of high-risk pathologic features and thus facilitate treatment decisions. (C) 2022 by the American Academy of Ophthalmology.

Purpose:The purpose of this study was to analyze trends in number, age-adjusted frequency, and type of keratoplasty in a major tertiary referral center, relative to patient and graft characteristics.Methods:A retrospective registry study of 1574 patients who in 1995 to 2015 underwent keratoplasty in the Helsinki University Eye Hospital (HUEH). Graft type and sequence, patient characteristics, and date of surgery were recorded. Main outcome measures were annual number, type, and age-adjusted frequency of keratoplasty; patient and graft characteristics; graft procurement; and national population-adjusted frequency of keratoplasty.Results:In HUEH, from 1995 to 2015, a total of 2191 keratoplasties were performed with 48% of the grafts procured intramurally; 76% were primary and 24% regrafts. The age-adjusted frequency of primary penetrating keratoplasty decreased by 52% from 0.96 to 0.46 per 100,000. The corresponding frequency of primary Descemet stripping automated endothelial keratoplasty increased by 367% from 0.3 to 1.4 after 2006, finally accounting for 68% of primary grafts. Men underwent primary penetrating keratoplasty (median 48 vs. 67 yrs, P = 0.0001) and anterior lamellar keratoplasty (median 37 vs. 46 yrs, P = 0.0015) at a younger age than women. Interval to the first regraft was comparable between sexes (median 2.2 vs. 1.9 yrs, respectively, P = 0.17). The national median population-adjusted frequency of keratoplasties was 3.2 per 100,000 from 2009 to 2015, and HUEH accounted for a median of 69% of them.Conclusions:The increased frequency of keratoplasty in HUEH resulted from rapid adoption of Descemet stripping automated endothelial keratoplasty after 2006 and was facilitated by centralizing graft procurement to HUEH and the National Cell and Tissue Center Regea.

Funding Information: Obtained funding: N/A; Study was performed as part of the regular employment duties of all authors at their institutions. No additional funding was provided. Non

OBJECTIVE: To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. METHODS: A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. RESULTS: For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p

Purpose: To compare tumor control, vision, and complications between patients with a choroidal melanoma of Design: Retrospective, comparative case series. Participants: One hundred sixty-four consecutive patients with a choroidal melanoma of Methods: Diagnosis was based on growth or high-risk characteristics. The apical dose was 100 to 120 Gy aiming to deliver >= 250 Gy to the sclera. Plaque positioning was modeled retrospectively. An increase of >= 0.3 mm in thickness and >= 0.5 mm in LBD indicated local recurrence. Outcomes were compared with cumulative incidence analysis and Cox regression. Median follow-up time for patients still alive was 8.4 years. Main Outcome Measures: Recurrence rate, low vision, blindness, radiation maculopathy, and optic neuropathy. Results: Melanomas treated with the 10-mm plaque were smaller (median thickness, 1.9 mm vs. 2.6 mm; LBD, 7.1 mm vs. 8.6 mm) and located closer to foveola (median, 2.0 mm vs. 2.8 mm) than those treated with the 15-mm plaque (P

Purpose: To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB). Design: International, multicenter, registry-based retrospective case series. Participants: A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Methods: International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included. Main Outcome Measures: Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC). Results: Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2- and 5-year KaplaneMeier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P

The authors regret that Science Direct is not formatted to display the full content of the paper synopsis. This is now fixed with the publication of this corrigendum. List of contents 1. Introduction2. Epidemiology 2.1. Incidence2.2. Prevalence2.3. Predisposing factors for sporadic retinoblastoma3. Diagnosis 3.1. Presenting features3.2. Clinical examination and ancillary testing 3.2.1. Fundus documentation and fluorescein angiography3.2.2. Ultrasonic biomicroscopy (UBM)3.2.3. Optic coherence tomography (OCT)3.2.4. Magnetic Resonance Imaging (MRI)3.3. Classifications 3.3.1. Grouping of the eye at presentation (RE, IIRC, ICRB, COG, TNMH)3.3.2. Patient staging at presentation (IRSS, TNMH)3.3.3. Classification of retinoblastoma at relapse (RSU classification)3.4. Differential diagnosis3.5. Prenatal diagnosis of retinoblastoma3.6. Trilateral retinoblastoma 3.6.1. Incidence, early detection and screening3.6.2. Influence of the retinoblastoma treatment on the incidence of trilateral retinoblastoma3.6.3. Improved treatment of trilateral retinoblastoma: high-dose chemotherapy3.6.4. Differential diagnosis: pineal cysts3.7. Metastatic retinoblastoma 3.7.1. Diagnosis of metastatic retinoblastoma3.7.2. Treatment of metastatic retinoblastoma3.7.3. Influence of conservative retinoblastoma treatment in the occurrence of metastasis3.8. Second primary neoplasms 3.8.1. Incidence and mortality of second primary neoplasms3.8.2. Characteristics of secondary primary neoplasms3.8.3. Factors influencing the risk of secondary primary neoplasms 3.8.3.1. Genetic predisposition3.8.3.2. Influence of therapy3.8.3.2.1. Radiotherapy3.8.3.2.2. Chemotherapy3.8.4. Long-term follow-up in heritable retinoblastoma survivors 4. Retinoblastoma genesis 4.1. Mutational inactivation of the RB1 gene initiates retinoblastoma tumorigenesis4.2. Most retinoblastomas show more than two-hits4.3. RB1 mutations initiate tumorigenesis in the retinoblastoma cell-of-origin 4.3.1. First hints pointing towards a photoreceptor cell-of-origin4.3.2. Efforts to identify the retinoblastoma origin using genetically engineered mice4.3.3. Circumstantial and direct evidence for a cone precursor cell-of-origin4.3.4. Reconciling the cone precursor cell-of-origin with apparently contradictory observations4.4. Collaboration between RB1 inactivation and the cell-of-origin circuitry5. Retinoblastoma genetics and genetic counseling 5.1. Genetic presentations of retinoblastoma 5.1.1. Inherited heritable retinoblastoma (familial retinoblastoma) 5.1.1.1. Familial retinoblastoma with complete retinoblastoma5.1.1.2. Familial retinoblastoma with incomplete penetrance5.1.2. Isolated heritable retinoblastoma 5.1.2.1. Isolated bilateral retinoblastoma (full expressivity)5.1.2.2. Isolated retinoblastoma with genomic 13q14 deletion (reduced expressivity)5.1.3. Mosaic retinoblastoma5.1.4. Non-heritable retinoblastoma 5.1.4.1. Isolated unilateral retinoblastoma with somatic biallelic RB1 mutation5.1.4.2. Retinoblastoma without alterations of the RB1 gene 5.2. Genetic counseling and testing 5.2.1. Familial retinoblastoma5.2.2. Isolated bilateral retinoblastoma5.2.3. Isolated unilateral retinoblastoma 6. Clinical growth and seeding patterns 6.1. Retinoblastoma growth patterns 6.1.1. Classic growth patterns of primary retinoblastoma: endophytic, exophytic, mixed growth6.1.2. Rare variants of retinoblastoma 6.1.2.1. Cavitary retinoblastoma6.1.2.2. Diffuse infiltrating retinoblastoma6.1.2.3. Diffuse anterior retinoblastoma 6.2. Intra-ocular seeding 6.2.1. Vitreous seeding6.2.2. Retrohyaloid seeding6.2.3. Subretinal seeding6.2.4. Aqueous seeding 6.2.4.1. Prevalence of anterior chamber seeding6.2.4.2. Prevalence of anterior uvea invasion6.2.4.3. Invasion mechanisms of the aqueous humor 6.3. Retinoma/retinocytoma and phthisis bulbi 6.3.1. Prevalence and relationship with retinoblastoma6.3.2. Clinical features and risk of malignant transformation. 7. Conservative management of intraocular retinoblastoma 7.1. Pharmacokinetics 7.1.1. Intravenous drug delivery7.1.2. Intra-arterial drug delivery 7.1.2.1. Intraocular distribution of intra-arterial melphalan and topotecan7.1.2.2. Systemic adverse effects of intra-arterial delivered drugs7.1.3. Intravitreal drug delivery 7.1.3.1. Intraocular distribution of intravitreal melphalan7.1.3.2. Intraocular distribution of intravitreal topotecan7.1.4. Intracameral drug delivery7.1.5. Periocular drug delivery7.1.6. Suprachoroidal drug delivery7.2. Treatment modalities 7.2.1. Intravenous chemotherapy 7.2.1.1. Drug regimen and number of cycles7.2.1.2. Indications 7.2.1.2.1. Current indications7.2.1.2.2. Potential future indications 7.2.2. Treatment outcomes of intravenous chemotherapy 7.2.2.1. Relapse rate and role of consolidation by focal treatments7.2.2.2. Eye preservation without external beam radiotherapy7.2.3. Chemotherapy-related toxicity of intravenous chemotherapy 7.2.3.1. Expected toxicities7.2.3.2. Long-term toxicities7.2.4. Intra-arterial chemotherapy 7.2.4.1. Drug regimen and number of cycles7.2.4.2. Indications 7.2.4.2.1. Current indications7.2.4.2.2. Potential future indications7.2.4.3. Treatment outcomes 7.2.4.3.1. Recurrence rate and salvage therapy7.2.4.3.2. Eye preservation without external beam radiotherapy7.2.4.4. Adverse effects7.2.5. Intravitreal chemotherapy 7.2.5.1. Drug regimen and number of injections7.2.5.2. Safety7.2.5.3. Treatment outcomes7.2.5.4. Adverse effects7.2.6. Intracameral chemotherapy 7.2.6.1. Treatment outcomes7.2.6.2. Treatment-related adverse effects7.2.6.3. Potential alternatives to intracameral chemotherapy for aqueous seeding7.2.7. Periocular chemotherapy7.2.8. Focal treatments 7.2.8.1. Cryotherapy7.2.8.2. Hyperthermia7.2.8.3. Photocoagulation7.2.8.4. Brachytherapy 7.3. Disease and treatment-related complications 7.3.1. Amblyopia7.3.2. Cataract 7.3.2.1. Incidence7.3.2.2. Cataract surgery7.3.3. Rhegmatogenous retinal detachment 7.3.3.1. Incidence7.3.3.2. Surgical repair7.3.4. Secondary neovascularization7.3.5. Chorioretinal complications 7.3.5.1. Intravitreal melphalan-induced chorioretinopathy 7.3.5.1.1. Clinical presentation, classification system and incidence7.3.5.1.2. Risk factors associated with intravitreal melphalan-induced chorioretinopathy 7.3.5.1.2.1. Intravitreal concentration7.3.5.1.2.2. Para-vitreal injections7.3.5.1.2.3. Intraocular pigmentation7.3.5.1.2.4. Concomitant drug interactions 7.3.5.2. Choroidal occlusive vasculopathy 7.3.5.2.1. Clinical presentation, classification system and incidence.7.3.5.2.2. Factors associated with choroidal occlusive vasculopathy 7.4. Evaluation of quality of life8. Future directions and conclusion 8.1. Animal models8.2. Gene therapy8.3. Cell-of-origin targeted therapy8.4. Personalized therapy and liquid biopsy8.5. New drugs or combinations of drugs8.6. New Galenic formulation of known drugs8.7. Conclusion

TOPIC: To determine the age up to which children are at risk of trilateral retinoblastoma (TRb) developing, whether its onset is linked to the age at which intraocular retinoblastomas develop, and the lead time from a detectable pineal TRb to symptoms.CLINICAL RELEVANCE: Approximately 45% of patients with retinoblastoma-those with a germline RB1 pathogenic variant-are at risk of pineal TRb developing. Early detection and treatment are essential for survival. Current evidence is unclear regarding the usefulness of screening for pineal TRb and, if useful, the age up to which screening should be continued.METHODS: We conducted a study according to the Meta-analysis of Observational Studies in Epidemiology guidelines for reporting meta-analyses of observational studies. We searched PubMed and Embase between January 1, 1966, and February 27, 2019, for published literature. We considered articles reporting patients with TRb with survival and follow-up data. Inclusion of articles was performed separately and independently by 2 authors, and 2 authors also independently extracted the relevant data. They resolved discrepancies by consensus.RESULTS: One hundred thirty-eight patients with pineal TRb were included. Of 22 asymptomatic patients, 21 (95%) were diagnosed before the age of 40 months (median, 16 months; interquartile range, 9-29 months). Age at diagnosis of pineal TRb in patients diagnosed with retinoblastoma at 6 months or younger versus older than 6 months were comparable (P = 0.44), suggesting independence between the ages at diagnosis of intraocular retinoblastoma and pineal TRb. The laterality of intraocular retinoblastoma and its treatment were not associated with the age at which pineal TRb was diagnosed. The lead time from asymptomatic to symptomatic pineal TRb was approximately 1 year. By performing a screening magnetic resonance imaging scan every 6 months after the diagnosis of heritable retinoblastoma (median age, 6 months) until 36 months of age, at least 311 and 776 scans would be required to detect 1 case of asymptomatic pineal TRb and to save a single life, respectively.CONCLUSIONS: Patients with retinoblastoma are at risk of pineal TRb developing for a shorter period than previously assumed, and the age at diagnosis of pineal TRb is independent of the age at diagnosis of retinoblastoma. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) level of evidence for these conclusions remains low.

From 7% to 10% of all retinoblastomas and from 44% to 71% of familial retinoblastomas in developed countries are diagnosed in the neonatal period, usually through pre- or post-natal screening prompted by a positive family history and sometimes serendipitously during screening for retinopathy of prematurity or other reasons. In developing countries, neonatal diagnosis of retinoblastoma has been less common. Neonatal retinoblastoma generally develops from a germline mutation of RB1, the retinoblastoma gene, even when the family history is negative and is thus usually hereditary. At least one-half of infants with neonatal retinoblastoma have unilateral tumors when the diagnosis is made, typically the International Intraocular Retinoblastoma Classification (Murphree) Group B or higher, but most germline mutation carriers will progress to bilateral involvement, typically Group A in the fellow eye. Neonatal leukokoria usually leads to the diagnosis in children without a family history of retinoblastoma, and a Group C tumor or higher is typical in the more advanced involved eye. Almost all infants with neonatal retinoblastoma have at least one eye with a tumor in proximity to the foveola, but the macula of the fellow eye is frequently spared. Consequently, loss of reading vision from both eyes is exceptional. A primary ectopic intracranial neuroblastic tumor known as trilateral retinoblastoma is no more common after neonatal than other retinoblastoma. For many reasons, neonatal retinoblastoma may be a challenge to eradicate, and the early age at diagnosis and relatively small tumors do not guarantee the preservation of both eyes of every involved child. Oncology nurses can be instrumental in contributing to better outcomes by ensuring that hereditary retinoblastoma survivors receive genetic counseling, by referring families of survivors to early screening programs when they are planning for a baby, and by providing psychological and practical support for parents when neonatal retinoblastoma has been diagnosed.

English summary

Purpose: To estimate the population-based incidence of acute idiopathic optic neuritis (ON) and analyse its differential diagnosis in patients referred with symptoms suggestive of ON. Methods: Patients with suspected ON referred to the Helsinki University Hospital, serving a population of 1.5 million in Southern Finland, were reviewed between 1st May 2008 and 14th April 2012. Brain and optic nerve magnetic resonance imaging (MRI) was performed within 24 hours in 83% of patients. Results: Of 291 referred patients, 184 (63%; 95% confidence interval [CI], 57–69%) were diagnosed with ON whereas 107 (37%) had another condition. The estimated crude incidence of ON in Southern Finland was 3.0 (95% CI 2.8–3.3) per 100,000 (females, 4.6 and males, 1.4). Mean age was 34 years (range 15–61), 76% were female. Two (1%) were diagnosed with neuromyelitis optica. ON as the first demyelinative episode was diagnosed in 108 (59%) patients, and MRI showed demyelinating lesions (MRI+) in 82% (95% CI, 75–89) of them. MRI+ predicted the development of multiple sclerosis (MS): 54% of MRI+ vs. 5% MRI− patients were diagnosed as MS during a mean follow-up of 7.7 years. The most common differential diagnosis was non-arteritic anterior ischemic optic neuropathy (12%). Six (2%) intracranial compressive lesions were found upon MRI scan. Conclusions: More than a third of patients with symptoms suggestive of ON had another condition. Demyelinative lesions on MRI indicated higher risk of developing MS. We recommend the use of MRI to improve the differential diagnostic accuracy of ON and to identify patients with high risk of MS.