Диагностическая полезность индекса свободной цепи света в Каппе у взрослых с оптовым неритом.

Introduction

In adults, optic neuritis (ON) is frequently the first clinical presentation of multiple sclerosis (MS), myelin oligodendrocyte glycoprotein antibody (MOG-IgG)–associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD). At the acute phase of inaugural ON (ION), several clinical, MRI, and biological features can help differentiate these diagnoses. 1-7 Particularly, unilateral mild impaired visual acuity, no or mild optic disc edema, multifocal T2 hyperintense brain white matter lesions, and oligoclonal bands (OCBs) in the CSF are more suggestive of MS. By contrast, severe reduced visual acuity, bilateral clinical involvement, and longitudinal optic nerve involvement are more suggestive of MOGAD or NMOSD. Finally, perineural optic sheath enhancement and optic disc edema are more suggestive of MOGAD while involvement of the posterior part of the optic nerve and the chiasma are more suggestive of NMOSD.

Nevertheless, suggestive features may be lacking and differentiation of conditions could be difficult in some patients. Hence, physicians perform serum anti-MOG/AQP4 antibody testing when MS criteria are not fulfilled and when patients experience some clinical/MRI features suggestive of MOGAD/NMOSD. This strategy is costly and results in uncertainty about a potential MOGAD/NMOSD diagnosis until test results are received, which could take several weeks. Thus, an accessible and less expensive biomarker with high accuracy that allows for ruling out MOGAD and/or NMOSD at ION would be of value to limit costs related to indiscriminate antibody testing. Moreover, this could improve the early management of ION because the time from symptom onset of ON to the administration of high-dose IV methylprednisolone significantly affects visual recovery in patients with MOGAD and NMOSD. 8,9

Previous studies demonstrated very low frequency of OCBs in the CSF of patients with MOGAD. 10-15 In addition, recent studies reported that the kappa free light chain (K-FLC) index in CSF could be a valid alternative to OCB testing for the diagnosis of MS, offering a quantitative, easy-to-perform, and cost-saving procedure. 16-24 More specifically, a recent study suggested that the K-FLC index may be a promising biomarker to help differentiate between MOGAD, NMOSD, and MS in patients. 25 Most patients with MOGAD had a K-FLC index under the lowest cutoff value previously reported for MS. By contrast, patients with NMOSD frequently had an elevated K-FLC index, and differentiation from MS could be difficult. However, the design of the study did not allow for testing the diagnostic accuracy of the K-FLC index and determining the best cutoff value to differentiate these diagnoses and MS because it did not include patients with MS and clinically isolated syndrome (CIS) suggestive of MS. Moreover, the study did not specifically focus on ION, which could be associated with more limited alteration in the K-FLC index compared with an inaugural parenchymal presentation of MOGAD/NMOSD or MS.

This retrospective study sought to determine the accuracy of the K-FLC index to differentiate between MOGAD or NMOSD and MS in patients with ION.

Methods

Protocol and Patients

We included all consecutive adult patients admitted to the MS center of the university hospital of Marseille from March 2016 to April 2024 for ION, with a CSF examination including K-FLC index measurement. To classify patients, we used the 2017 McDonald MS criteria, the international MOGAD Panel–proposed criteria, and the 2015 international consensus diagnostic criteria for NMOSD. 1,2,26 Among patients with a diagnosis of CIS at ION, those with future conversion to MS reported in their medical chart were classified as CIS with future conversion to MS (CISwc). We retained the diagnosis of other inflammatory disorders (OIDs) based on the final diagnosis reported in the medical chart.

Cell-Based Assays for Serum Anti-MOG and Anti-AQP4 Antibody Testing

MOG antibodies were analyzed at the university hospital of Lyon by an in-house method. 27 In brief, HEK293 cells were transfected (tHEK293) with pEGFP-N1-hMOG plasmid for 48 hours and then incubated with the patient's serum. Bound IgG was detected with a fluorescent secondary antibody, APC-goat anti-human IgG-Fcγ fragment-specific (1:100 dilution, Jackson ImmunoResearch). Non-tHEK293 cells were negative controls. Signal intensity was evaluated by flow cytometry. AQP4 antibodies were analyzed by living cell technique using flow cytometry, with transfection for the expression of the AQP4-M23 isoform. 28

K-FLC Determination

The K-FLC index and albumin and IgG levels in serum or CSF were measured using turbidimetry with the binding site reagents on Optilite (Thermo Fisher Scientific). 19 For increased sensitivity on the FLC assays, antiserum was linked to latex beads. The detection limit for K-FLC is 0.33 mg/L. The assessment of blood-CSF barrier permeability was estimated using the albumin-CSF/serum albumin ratio, whose normal value progressively increases with age (<6.3 × 10 −3 in adults). The K-FLC index is calculated according to the formula (CSF K-FLC [mg/L]/serum K-FLC [mg/L]) × (serum albumin [g/L]/CSF albumin [mg/L]).

MRI

Most MRI examinations performed in patients admitted to the MS center of the university hospital of Marseille included a 3D fluid-attenuated inversion recovery (FLAIR) sequence (1 mm 3 isotropic) for the brain and a short tau inversion recovery (STIR) sequence for the spinal cord. Dedicated sequences of the optic nerve, including T2FS/DIXON, 3D constructive interference in steady state (CISS), or volumetric interpolated breath-hold examination (VIBE) sequences, were also frequently obtained. All brain MRI scans showing brain parenchymal lesions other than nonspecific white matter (WM) changes—defined as small, rounded WM hyperintensities on T2/FLAIR sequences that did not meet the imaging characteristics or criteria for MS—were considered abnormal. Similarly, all spinal cord MRI scans revealing at least 1 lesion were classified as abnormal.

Statistical Analysis

Clinical, MRI, and biological characteristics were compared by the Fisher exact test for categorical variables and the Kruskal-Wallis test for continuous variables. The Dunn test was used to explore pairwise group differences in case of a significant Kruskal-Wallis result. We determined the sensitivity and specificity for categorical variables and the receiver operating characteristic (ROC) curve to assess the diagnostic ability of the K-FLC index for continuous variables (area under the ROC curve [AUC]). Finally, we performed multivariate logistic regression, including age, sex, the time between lumbar puncture and the first symptom, and steroid use before puncture, to test whether the diagnostic ability of the K-FLC index remained significant after adjustment for these potential confounders.

Standard Protocol Approvals, Registrations, and Patient Consents

The authors obtained ethical approval from the institutional review board of the university hospital of Marseille for this study (approval no. PADS-24-71).

Data Availability

All data analyzed during this study will be shared anonymized by reasonable request of a qualified investigator to the corresponding author.

Results

Study Population and Clinical Characteristics of Patients

A total of 227 adults were admitted to the MS center of Marseille for ION from March 2016 to April 2024; 210 (93%) had a K-FLC index measurement. All patients had a diagnosis of ON reported in their medical chart. All these diagnoses were established by an ophthalmologist of the university hospital of Marseille. Retrospective application of the proposed criteria of ON published in 2021 29 showed that 140 patients (67%) fulfilled the criteria for definite ON and 40 (19%) possible ON; application of these criteria was not possible in 30 patients (14%) because of insufficient information in the medical chart. A total of 201 patients (96%) underwent brain MRI, and 181 of these (86%) also had spinal cord MRI. Of the total, 178 patients (85%) had a 3D FLAIR or 2D FLAIR sequence with a dedicated protocol for the optic nerve (T2FS/Dixon, 3D CISS, or VIBE) and 140 (67%) had spinal cord MRI that included a STIR sequence.

MS was diagnosed in 84 patients (40%); CIS suggestive of MS in 77 (36.5%); MOGAD in 26 (12%); NMOSD in 13 (6%), including 5 with seronegative NMOSD; and OIDs in 10 (5%) ( Table 1 ). The mean (SD) follow-up of patients with CIS was 19 (19.5) months. During follow-up, 20 of the 77 patients with CIS showed conversion to MS according to the 2017 McDonald MS criteria. 26 These 20 patients were classified as having CIS with conversion (CISwc). All patients classified as having CIS (n = 77) were tested for anti-MOG and anti-AQP4 antibodies: 1 was positive for anti-MOG antibodies at ION but was finally classified as having CISwc because brain MRI performed during follow-up revealed asymptomatic accumulation of demyelinating lesions fulfilling the 2017 McDonald MS criteria. 26 This patient exhibited no clinical or MRI findings suggestive of MOGAD, and CSF analysis revealed the presence of OCBs, an IgG index of 1, and a K-FLC index of 101. OIDs included 3 cases of sarcoidosis, 1 case of anti-PD1 complication, 1 case of anti-IGLON5 encephalitis, and 5 cases of nonclassified inflammatory CNS pathology. Of the 5 patients diagnosed with seronegative NMOSD, 3 exhibited other core clinical characteristics confirmed by MRI concomitant with ION while 2 developed such characteristics during follow-up. Demographic and clinical characteristics of the groups are given in Table 1 .

Table 1 Clinical, Radiologic, and Biological Characteristics of Patients at Inaugural Optic Neuritis All patients (n = 210) MS (n = 84) (40%) CIS (n = 77) (36.5%) Mean (SD) follow-up, 19 (19.5) mo MOGAD (n = 26) (12.5%) NMOSD (n = 13) (6%) OIDs (n = 10) (5%) Without conversion to MS (n = 57) With conversion to MS (n = 20) Age, y, mean (SD), median (range) 35 (12), 32 (18–83) 31 (10), 28 (18–68) 36 (11), 34 (18–65) a 35 (9), 33 (22–52) 42 (15), 39 (18–70) b 39 (15), 33 (25–71) 39 (21), 32 (18–83) Female, n (%) 108 (51) 43 (51) 31 (54) 12 (60) 10 (38.5) 11 (85) a 1 (10) a High-contrast BCVA at nadir, logMAR, median (range) 0.65 (0–2.7) 0.5 (0–2.7) 0.3 (0–2.7) 1.4 (0–2.7) 1.3 (0–2.7) b 2.7 (0.3–2.7) c 0.4 (0–1.4) Bilateral presentation, n/total available (%) 24/210 (11) 3/84 (3.5) 3/57 (5) 0/20 (0) 11/26 (42) c 5/13 (38) c 2/10 (20) c Optic disc edema, n/total available (%) 64/169 (38) 18/72 (25) 12/32 (37) 7/19 (37) 19/25 (76) c 3/12 (25) 5/9 (55) RNFL (worst eye), median (range) 129 (77–275) 108 (77–200) 121 (113–181) 125 (88–200) 150 (89–275) a 100 (78–185) 171 (167–252) a Presence of inflammatory lesions of the brain/spinal cord, n/total available (%) 105/201 (52) 84/84 (100) 0/52 (0) c 13/20 (65) c 0/24 (0) c 5/12 (41) c 3/9 (33) c CSF findings  Cells/mm3, median (range) 1 (0–81) 3 (0–78) 0 (0–81) b 2 (0–19) 1 (0–20) 3.5 (0–41) 2.5 (0–18)  Protein/mm3, median (range) 0.32 (0.13–1.21) 0.33 (0.14–0.76) 0.31 (0.15–0.95) 0.29 (0.13–0.74) 0.33 (0.14–1.21) 0.41 (0.19–0.7) 0.36 (0.19–0.7)  Presence of oligoclonal bands, n/total available (%) 115/197 (58) 83/84 (99) 7/50 (14) c 18/19 (95) 2/23 (9) c 5/13 (38) c 0/10 (0) c  IgG index, median (range) 0.63 (0.18–3.63) 0.82 (0.18–3.63) 0.52 (0.3–0.93) c 0.74 (0.51–2.58) 0.54 (0.42–0.92) c 0.57 (0.2–0.95) c 0.6 (0.41–0.98) c  K-FLC index, median (range) 11 (0–394) 55 (0–394) 0 (0–76) c 26 (4–138) 0 (0–16) c 6 (0–48) c 0 (0–11) c Abbreviations: AQP4 = aquaporin-4; BCVA = best-corrected visual acuity; CIS = clinically isolated syndrome; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NMOSD = neuromyelitis optica spectrum disorder; OIDs = other inflammatory disorders; RNFL = retinal nerve fiber layer. Statistical comparisons were performed with the MS group as reference. a <0.05. b <0.01. c <0.001.

Clinical, Radiologic, and Biological Characteristics of Patients at Inaugural Optic Neuritis

Abbreviations: AQP4 = aquaporin-4; BCVA = best-corrected visual acuity; CIS = clinically isolated syndrome; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NMOSD = neuromyelitis optica spectrum disorder; OIDs = other inflammatory disorders; RNFL = retinal nerve fiber layer.

Statistical comparisons were performed with the MS group as reference.

<0.05.

<0.01.

<0.001.

Comparison of CSF Findings Between Groups

The proportion of OCBs for MS, CIS without conversion, CISwc, MOGAD, seronegative NMOSD, AQP4+NMOSD, and OID groups was 99%, 14%, 95%, 8.5%, 20%, 50%, and 0%, respectively. Most cases with positive OCBs were type 2, with only a few cases of type 3. The median (range) K-FLC index for MS, CIS without conversion, CISwc, MOGAD, seronegative NMOSD, AQP4+NMOSD, and OID groups was 55.5 (0–394), 0 (0–76), 26 (4–138), 0 (0–16), 4 (0–47.5), 16 (0–40), and 0 (0–11), respectively ( Table 1 , Figure 1 ).

Comparison of CSF Findings Between Groups

Violin plots of (A) IgG index values for each group at inaugural optic neuritis and (B) kappa free light chain index values for each group.

Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating Diagnoses in Patients With ION

Differentiation Between MS/CISwc and All Other Diagnoses (MOGAD, NMOSD, CIS, and OIDs)

Accuracies of clinical characteristics and MRI and CSF findings for differentiating MS/CISwc from all other diagnoses (MOGAD, NMOSD, CIS, and OIDs) are provided in Table 2 . Regarding the accuracy of the K-FLC index, the ROC curve gave an AUC of 0.94 to differentiate MS/CISwc from other diagnoses, with a best cutoff of 6.7. A K-FLC index ≥6.7 allowed for distinguishing patients with MS/CISwc and those with other diagnoses, with specificity 86% and sensitivity 95%. On multivariable regression analysis, including age, sex, the time between lumbar puncture and the first symptom, steroid use before lumbar puncture, and binary K-FLC index (based on the obtained threshold value of 6.7) as explanatory variables and diagnoses (MS/CISwc vs other diagnoses) as the dependent variable, the K-FLC index was significantly associated with the diagnoses ( p < 0.001).

Table 2 Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating MS/CISwc From All Other Diagnoses (MOGAD, NMOSD, CIS, and OIDs) In favor of all other diagnoses (MOGAD, NMOSD, CIS, and OIDs) (n = 106) vs MS/CISwc (n = 104) Best cutoff AUC Sensitivity (%) Specificity (%) Bilateral ON NA NA 20 97 Presence of optic disc edema NA NA 50 72 High-contrast BCVA at nadir (logMAR) ≥2.7 0.53 21 89 In favor of MS/CISwc (n = 104) vs all other diagnoses (MOGAD, NMOSD, CIS, and OIDs) (n = 106) Best cutoff AUC Sensitivity (%) Specificity (%) Abnormal brain and spinal cord MRI NA NA 93 92 CSF IgG index ≥0.62 0.88 88 75 Presence of OCBs in CSF NA NA 98 85 CSF K-FLC index ≥6.7 0.94 95 86 Abbreviations: BCVA = best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating MS/CISwc From All Other Diagnoses (MOGAD, NMOSD, CIS, and OIDs)

Abbreviations: BCVA = best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Differentiation Between MOGAD and All Other Diagnoses (MS/CISwc, NMOSD, CIS, and OIDs)

Accuracies of clinical characteristics and MRI and CSF findings for differentiating MOGAD from all other diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) are provided in Table 3 . Regarding accuracy of the K-FLC index, the ROC curve gave an AUC of 0.78 for differentiating MOGAD from other diagnoses with a best cutoff of 4.9. A K-FLC index <4.9 allowed for distinguishing patients with MOGAD and those with other diagnoses, with specificity 63% and sensitivity 92%. Overall, 24 of 26 patients with MOGAD (92%) had a K-FLC index <4.9. Two patients with MOGAD had a K-FLC index ≥4.9, 1 with a value of 7.9 and the other 16.2. The patient with a K-FLC index of 7.9 exhibited severe visual acuity loss of 1.4 logMAR and papillary edema, whereas the patient with a K-FLC index of 16.2 showed a less severe visual acuity loss of 0.7 logMAR without papillary edema. Among all patients with ION included (n = 210), 93 (44%) had a K-FLC index <4.9. In these patients, serum anti-MOG antibody testing was positive for 26%. Among the remaining 117 patients with a K-FLC index ≥4.9, 2 (1.7%) had a diagnosis of MOGAD (K-FLC index at 7.9 and 16.2). On multivariable regression analysis, including age, sex, the time between lumbar puncture and the first symptom, steroid use before lumbar puncture, and binary K-FLC index (based on the obtained threshold value of 4.9) as explanatory variables and diagnoses (MOGAD vs other diagnoses) as the dependent variable, the K-FLC index was significantly associated with the diagnoses ( p < 0.001).

Table 3 Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating MOGAD From All Other Diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) and MOGAD From MS/CISwc in Patients With Inaugural Optic Neuritis In favor of MOGAD (n = 26) vs all other diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) (n = 184) In favor of MOGAD (26) vs MS/CISwc (n = 104) Best cutoff AUC Sensitivity (%) Specificity (%) Best cutoff AUC Sensitivity (%) Specificity (%) Bilateral ON NA NA 42 93 NA NA 42 97 Presence of optic disc edema NA NA 76 69 NA NA 76 73 Normal brain and spinal cord MRI NA NA 100 59 NA NA 100 93 High-contrast BCVA at nadir (logMAR) ≥0.7 0.65 79 54 ≥0.6 0.66 79 53 CSF IgG index <0.64 0.71 88 52 <0.64 0.88 88 77 Absence of OCBs in CSF NA NA 91 65 NA NA 91 98 CSF K-FLC index <4.9 0.78 92 63 <4.9 0.97 92 96 Abbreviations: BCVA = best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating MOGAD From All Other Diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) and MOGAD From MS/CISwc in Patients With Inaugural Optic Neuritis

Abbreviations: BCVA = best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Differentiation Between MOGAD and All Other Diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) in the Subgroup of Patients With Normal Brain and Spinal Cord MRI Findings

Among all the patients with ION included (n = 210), 96 (48%) had normal brain and spinal cord MRI findings, including all patients with MOGAD with MRI examinations available (n = 24). Accuracies of clinical characteristics and MRI and CSF findings for differentiating MOGAD from all other diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) in patients with normal brain and spinal cord MRI findings are provided in Table 4 . Regarding the K-FLC index, the ROC curve gave an AUC of 0.58 for differentiating MOGAD from other diagnoses of ION with normal MRI findings. A K-FLC index <4.9 allowed for distinguishing patients with MOGAD and those with other diagnoses of ION with normal MRI findings, with specificity 29% and sensitivity 92%. Among patients with normal MRI findings (n = 96), 73 (76%) had a K-FLC index <4.9: 22 of these (30%) had MOGAD, and none showed conversion to MS. In the remaining patients with a K-FLC index ≥4.9 (n = 23), 2 (8.5%) had MOGAD and 7 (30.5%) showed conversion to MS.

Table 4 Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating MOGAD From All Other Diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) in Patients With Normal Brain and Spinal Cord MRI In favor of MOGAD (n = 24) vs all other diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) (n = 72) in patients with normal brain and spinal cord MRI Best cutoff AUC Sensitivity (%) Specificity (%) Bilateral ON NA NA 37 93 Presence of optic disc edema NA NA 78 60 High-contrast BCVA at nadir (logMAR) ≥0.7 0.65 78 57 CSF IgG index <0.57 0.51 70 47 Absence of OCBs in CSF NA NA 91 25 CSF K-FLC index <4.9 0.58 92 29 Abbreviations: BCVA = best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating MOGAD From All Other Diagnoses (MS/CISwc, NMOSD, CIS, and OIDs) in Patients With Normal Brain and Spinal Cord MRI

Abbreviations: BCVA = best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

On multivariable regression analysis, including age, sex, the time between lumbar puncture and the first symptom, steroid use before lumbar puncture, and binary K-FLC index (based on the obtained threshold value of 4.9) as explanatory variables and diagnoses as the dependent variable (MOGAD vs those with other diagnoses of ION with normal MRI findings), the K-FLC index was significantly associated with the diagnoses ( p < 0.05).

Differentiation Between MOGAD and MS/CISwc

Accuracies of clinical characteristics and MRI and CSF findings for differentiating MOGAD from MS/CISwc are provided in Table 3 . Regarding the K-FLC index, the ROC curve gave an AUC of 0.97 for differentiating MOGAD from MS/CISwc, with a best cutoff of 4.9 ( Figure 2 ). A K-FLC index <4.9 allowed for distinguishing patients with MOGAD and those with MS/CISwc, with specificity 96% and sensitivity 92%. In total, 24 of 26 patients with MOGAD (92%) and 5 of 104 with MS/CISwc (5%) had a K-FLC index <4.9. On multivariable regression analysis, including age, sex, the time between lumbar puncture and the first symptom, steroid use before lumbar puncture, and binary K-FLC index (based on the obtained threshold value of 4.9) as explanatory variables and diagnoses (MOGAD vs those with MS/CISwc) as the dependent variable, the K-FLC index was significantly associated with the diagnoses ( p < 0.001).

Discrimination Between MOGAD and MS/CISwc

ROC curve for the IgG index gave an AUC of 0.88 with a best cutoff of 0.64. ROC curve for the K-FLC index gave an AUC of 0.97 with a best cutoff of 4.9. AUC = area under the curve; MOGAD = =myelin oligodendrocyte glycoprotein antibody–associated disease; ROC = receiver operating characteristic.

Differentiation Between NMOSD and All Other Diagnoses (MOGAD, MS/CISwc, CIS, and OIDs)

Accuracies of clinical characteristics and MRI and CSF findings for differentiating NMOSD from all other diagnoses (MS/CISwc, MOGAD, CIS, and OIDs) are provided in Table 5 . Regarding the K-FLC index, the ROC curve gave an AUC of 0.50 for differentiating NMOSD from other diagnoses, with a best cutoff of 52.5. A K-FLC index <52.5 allowed for distinguishing patients with NMOSD and those with other diagnoses, with specificity 25% and sensitivity 100%. On multivariable regression analysis, including age, sex, the time between lumbar puncture and the first symptom, steroid use before lumbar puncture, and binary K-FLC index (based on the obtained threshold value of 52.5) as explanatory variables and diagnoses (NMOSD vs other diagnoses) as the dependent variable, the K-FLC index was significantly associated with the diagnoses ( p < 0.01).

Table 5 Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating NMOSD From All Other Diagnoses (MS/CISwc, MOGAD, CIS, and OIDs) and NMOSD From MS/CISwc in Patients With Inaugural Optic Neuritis In favor of NMOSD (n = 13) vs all other diagnoses (MOGAD, MS/CISwc, CIS, and OIDs) (n = 197) In favor of NMOSD (n = 13) vs MS/CISwc (n = 104) Best cutoff AUC Sensitivity (%) Specificity (%) Best cutoff AUC Sensitivity (%) Specificity (%) Bilateral ON NA NA 38 90 NA NA 38 97 Presence of optic disc edema NA NA 25 61 NA NA 25 73 Normal brain and spinal cord MRI NA NA 58 53 NA NA 58 93 High-contrast BCVA at nadir (logMAR) ≥1.4 0.82 83 71 ≥2.7 0.82 67 89 CSF IgG index <0.65 0.63 77 46 <0.65 0.82 77 76 Absence of OCBs in CSF NA NA 62 60 NA NA 62 98 CSF K-FLC index <52.5 0.50 100 26 <6.7 0.80 54 95 Abbreviations: BCVA: best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Accuracy of Clinical Characteristics and MRI and CSF Findings for Differentiating NMOSD From All Other Diagnoses (MS/CISwc, MOGAD, CIS, and OIDs) and NMOSD From MS/CISwc in Patients With Inaugural Optic Neuritis

Abbreviations: BCVA: best-corrected visual acuity; CISwc = clinically isolated syndrome with conversion to MS; MOG = myelin oligodendrocyte glycoprotein; MOGAD = MOG antibody–associated disease; MS = multiple sclerosis; NA = not applicable; NMOSD = neuromyelitis optica spectrum disorder; OCBs = oligoclonal bands.

Differentiation Between NMOSD and MS/CISwc

Accuracies of clinical characteristics and MRI and CSF findings for differentiating NMOSD from MS/CISwc are provided in Table 5 . Regarding the K-FLC index, the ROC curve gave an AUC of 0.80 for differentiating NMOSD from MS/CISwc, with a best cutoff 6.7. A K-FLC index <6.7 allowed for distinguishing patients with NMOSD and those with MS/CISwc, with specificity 95% and sensitivity 54%. On multivariable regression analysis, including age, sex, the time between lumbar puncture and the first symptom, steroid use before lumbar puncture, and binary K-FLC index (based on the obtained threshold value of 6.7) as explanatory variables and diagnoses (NMOSD vs those with MS/CISwc) as the dependent variable, the K-FLC index was significantly associated with the diagnoses ( p < 0.005).

Discussion

This study included more than 90% of all consecutive adult patients with ION who were referred from March 2016 to April 2024 to the sole MS center of Marseille, the second most populated city of France, with arpproximately 1 million inhabitants. Hence, the study provides an accurate reflection of the incidence of the different etiologies of ION in adults within this specific geographic area. As previously reported, MS represents the most frequent etiology of ION, with 40% of patients fulfilling the 2017 McDonald MS criteria at ION. The second most frequent diagnosis was CIS, with 36.5% of patients, including 10% with conversion to MS. The remaining diagnoses were MOGAD, NMOSD, and OIDs, with 12.5%, 6%, and 5% of patients, respectively. These incidences are in line with previous studies. 30-32

This study confirmed that the K-FLC index showed very high accuracy (AUC 0.94) to differentiate MS/CISwc from all other inflammatory diseases of the CNS. In adults with ION, a K-FLC ≥6.7 differentiated MS/CISwc and other diagnoses, with specificity 86% and sensitivity 95%. These findings extend results obtained in patients with various clinical presentations to the specific context of ION. Notably, we identified a very similar optimal cutoff value for the K-FLC index as previously reported to discriminate MS. 23 Crucially, we found very high accuracy (AUC 0.97) for the K-FLC index to differentiate MS/CISwc from MOGAD, the 2 most frequent causes of ON. A K-FLC index <4.9 distinguished patients with MOGAD and those with MS/CISwc, with specificity 96% and sensitivity 92%, which is similar to the accuracy of OCBs, with specificity 98% and sensitivity 91%, for differentiating between these 2 diagnoses in patients with ION. Compared with OCBs, the K-FLC index measurement has methodological advantages. First, K-FLC index results can be obtained very quickly (even within an hour of sampling). The test is subject to little or no interlaboratory variation, unlike the detection of OCBs, where technical approaches may differ between laboratories. Moreover, the result is not influenced by subjective interpretation, unlike the interpretation of electrophoresis profiles. Finally, the K-FLC index has a lower cost compared with OCB determination. Thus, measuring the K-FLC index could provide an accurate tool to guide the early diagnosis of ION, which could be easily implemented in less specialized laboratories and in low-income countries.

In addition, the study assessed the accuracy of the K-FLC index for differentiating MOGAD from all other diagnoses in a context of ION. A K-FLC index <4.9 differentiated MOGAD from other diagnoses with high sensitivity (92%) and moderate specificity (63%). Among all the patients with ION we included (n = 210), less than half (n = 93) had a K-FLC index <4.9. In these patients, serum anti-MOG antibody testing was positive for 26%, which argues for the relevancy to perform MOG antibody testing in patients with ION and a K-FLC index <4.9. Conversely, among the remaining 117 patients with a K-FLC index ≥4.9, 87% were classified as having MS or demonstrated future conversion to MS and only 1.7% had a diagnosis of MOGAD. These results extend the recent results obtained in patients with CIS with various clinical presentations to patients with ION, thus revealing the high predictive value of the K-FLC index for future conversion to MS. 33 Crucially, the K-FLC index allows for distinguishing, at ION, patients with MOGAD and those with CISwc, including patients without any parenchymal demyelinating lesions at ION. Indeed, 35% of the patients with CISwc had normal MRI findings at the time of ION and all had a K-FLC index ≥4.9. In addition, among patients with normal MRI findings and a K-FLC index <4.9, serum anti-MOG antibody testing was positive for 30%. Among patients with normal MRI findings and a K-FLC index ≥4.9, 8.5% had a diagnosis of MOGAD and 30% demonstrated conversion to MS. This point is of major importance to guide anti-MOG antibody testing in patients with ION and normal MRI findings. 34 MOG antibody testing should not be performed in all patients with ION and normal MRI findings in case of a K-FLC index ≥4.9. In these patients, MOG antibody testing should be performed in case of severe loss of visual acuity, bilateral presentation, or severe papillary edema. Of note, the 2 patients with MOGAD and a K-FLC index ≥4.9 had a limited elevated index, at 7.9 and 16.2.

Finally, the K-FLC index seemed less efficient in differentiating NMOSD from MS or other diagnoses, as recently suggested. 25 Indeed, the median value of the K-FLC index was 5.9 (range 0–47.6) for patients with NMOSD. This heterogeneity was also present in patients with AQP4+NMOSD, with a median K-FLC index of 16 (range 0–40). The higher frequency of elevated K-FLC index in patients with NMOSD vs those with MOGAD could reflect histopathologic findings arguing for a lower number of B cells in the CNS lesions of MOGAD compared with NMO. 35-37 However, because of the limited number of patients with AQP4+NMOSD included, these results should be interpreted with caution.

The strengths of the study are the large sample of patients with ION included with standardized and exhaustive clinical and biological examinations including the K-FLC index and MOG/AQP4 antibody testing performed concomitantly. The limitations are the relatively small sample size of patients with MOGAD and NMOSD and the monocentric design.

This study demonstrates that the K-FLC index is a relevant biomarker to guide diagnosis at the time of ION. The probability of MOGAD diagnosis in patients with ION and a K-FLC index ≥4.9 is low in patients with ION, even with normal brain/spinal cord MRI findings. Among patients with ION and a K-FLC index ≥4.9 at ION, at least 87% already fulfilled MS criteria or showed conversion to MS and only 1.7% had MOGAD.

Glossary

area under the ROC curve

clinically isolated syndrome

clinically isolated syndrome with conversion to MS

fluid-attenuated inversion recovery

inaugural ON

kappa free light chain

MOG-associated disease

multiple sclerosis

neuromyelitis optica spectrum disorder

oligoclonal band

other inflammatory disorders

optic neuritis

receiver operating characteristic

short tau inversion recovery

white matter

Author Contributions

S. Demortiere: major role in the acquisition of data; analysis or interpretation of data. N. Stolowy: major role in the acquisition of data. M. Perriguey: major role in the acquisition of data. C. Boutiere: major role in the acquisition of data. A. Rico: Major role in the acquisition of data. F. Hilezian: major role in the acquisition of data. B.-R. Ndjomo-Ndjomo: major role in the acquisition of data. P. Durozard: major role in the acquisition of data. J.-P. Stellmann: major role in the acquisition of data. R. Marignier: major role in the acquisition of data. J. Boucraut: major role in the acquisition of data. J. Pelletier: major role in the acquisition of data. A. Maarouf: major role in the acquisition of data; study concept or design. B. Audoin: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data.

Study Funding

The authors report no targeted funding.

Disclosure

The authors report no relevant disclosures. Go to Neurology.org/N for full disclosures.

References

Associated Data

Data Availability Statement

All data analyzed during this study will be shared anonymized by reasonable request of a qualified investigator to the corresponding author.