Highlight
A recent multicenter retrospective study published in Neurology found that among patients presenting with inaugural acute optic neuritis who met the minimal 2017 McDonald criteria for multiple sclerosis (MS), 24% were ultimately diagnosed with an alternative antibody-mediated condition.
The study identified specific orbital MRI markers, including longitudinally extensive lesions, bilateral involvement, and optic perineuritis, as being 100% sensitive for non-MS diagnoses in this cohort.
The findings advocate for universal aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibody testing in all patients with inaugural optic neuritis, even when brain MRI findings appear to satisfy traditional MS criteria.
Background: The Evolution of Multiple Sclerosis Diagnostic Criteria
The diagnosis of multiple sclerosis has undergone significant refinement over the last two decades. The McDonald criteria were designed to facilitate early diagnosis by allowing clinicians to establish dissemination in space (DIS) and dissemination in time (DIT) using magnetic resonance imaging (MRI). The 2017 revision significantly increased the sensitivity of these criteria by allowing the presence of cerebrospinal fluid (CSF) oligoclonal bands to substitute for DIT and by including symptomatic lesions in the DIS count.
Recent updates have further expanded the role of the optic nerve. Historically, optic neuritis (ON) was the clinical gateway to an MS diagnosis but was not counted as a site of DIS. Newer consensus recommendations now include the optic nerve as a fifth anatomical site (joining the periventricular, cortical/juxtacortical, infratentorial, and spinal cord regions). While this increases diagnostic speed, it raises a critical clinical question: Does the inclusion of the optic nerve as a DIS site compromise diagnostic specificity? In the era of highly effective disease-modifying therapies (DMTs), distinguishing MS from its mimics—specifically Neuromyelitis Optica Spectrum Disorder (NMOSD) and MOG antibody-associated disease (MOGAD)—is more critical than ever.
Study Design and Methodology
To address this diagnostic tension, Deschamps and colleagues conducted a retrospective analysis across three major French medical centers. The study focused on a specific and highly relevant patient population: those with inaugural acute optic neuritis who met the most minimal requirements for a new MS diagnosis. Specifically, these patients had at least one MS-typical lesion in a single brain location on their baseline MRI, met the criteria for DIT (either through a second lesion or the presence of CSF-restricted oligoclonal bands), and utilized the optic nerve as the second site to satisfy DIS.
The cohort consisted of 96 patients with a mean age of 35.8 years, of whom 70.8% were female. All participants underwent standardized testing for AQP4 and MOG antibodies using cell-based assays, which are the gold standard for these conditions. The researchers then compared the initial diagnosis (based on minimal MS criteria) with the final diagnosis reached after longitudinal follow-up and comprehensive clinical and radiologic review.
Key Findings: The Prevalence of Non-MS Diagnoses
The results of the study are striking and provide a cautionary tale for early diagnosis. Out of the 96 patients who theoretically met the criteria for MS at onset, 23 (24.0%) were found to have an alternative diagnosis. Of these non-MS cases, 18 patients were diagnosed with MOGAD, and 5 were diagnosed with NMOSD (AQP4-antibody positive).
This means that nearly one out of every four patients who satisfy the minimal criteria for MS following an episode of optic neuritis actually has a distinct autoimmune pathology. This distinction is not merely academic; the treatment pathways for MS, NMOSD, and MOGAD differ significantly, and certain MS treatments (such as interferon-beta, fingolimod, and natalizumab) can potentially exacerbate NMOSD.
Clinical and Radiologic Predictors
A major strength of this study was the detailed analysis of orbital MRI features. The researchers sought to determine if specific imaging patterns could differentiate MS from its mimics at the time of the first event. They focused on several “red flag” features:
- Longitudinally extensive optic nerve lesions (involving more than half the length of the nerve).
- Bilateral optic nerve involvement.
- Chiasmal enhancement.
- Optic perineuritis (enhancement of the optic nerve sheath rather than the nerve itself).
The study found that 100% of the patients eventually diagnosed with MOGAD or NMOSD exhibited at least one of these patterns. In contrast, while these features were present in 24.6% of the MS patients, the absence of these specific MRI patterns was highly predictive of a true MS diagnosis. In fact, every single patient in the cohort who lacked these atypical orbital features was ultimately confirmed to have MS.
Expert Commentary: Balancing Sensitivity and Specificity
**Synthesizing the Data**
I’m now integrating the study’s results, like the 24% misdiagnosis rate, with the suggested structure, incorporating details on specific MRI features that accurately diagnose non-MS conditions. I will focus on the diagnostic implications, aiming for a detailed, clinically relevant summary.
The inclusion of the optic nerve in DIS criteria is a double-edged sword. On one hand, it allows for earlier initiation of DMTs in patients who truly have MS, which is known to improve long-term disability outcomes. On the other hand, this study highlights a significant risk of misdiagnosis. The 24% “false positive” rate for MS in this specific phenotype suggests that the minimal criteria may be too permissive if used in isolation.
Clinicians must maintain a high index of suspicion. The presence of optic perineuritis, for instance, is highly suggestive of MOGAD and is rarely seen in classic MS. Similarly, longitudinally extensive involvement of the optic nerve should immediately trigger antibody testing. However, the study also shows that even when these features are absent, the possibility of a non-MS diagnosis—though significantly lower—is not zero in the broader clinical context.
Furthermore, the presence of oligoclonal bands (OCBs) in the CSF, while a hallmark of MS, is not entirely exclusive. While OCBs are found in approximately 90% of MS patients, they can also be found in a small percentage of NMOSD and MOGAD cases, potentially leading to further diagnostic confusion if used as the sole confirmation of MS pathology.
Clinical Implications for Practice
Based on these findings, the following clinical pathway is recommended for patients presenting with inaugural optic neuritis:
1. Comprehensive Serology
All patients with acute ON should undergo AQP4 and MOG antibody testing using cell-based assays. This should be performed as early as possible, as antibody titers can sometimes decrease following high-dose corticosteroid treatment or plasma exchange.
2. Dedicated Orbital MRI
A standard brain MRI is often insufficient to capture the nuances of the optic nerve. Dedicated orbital sequences (with fat suppression and gadolinium enhancement) are essential to identify the “red flags” mentioned in the study, such as perineuritis or extensive longitudinal lesions.
3. Delayed Labeling
In cases where antibody results are pending, clinicians should be cautious about formally labeling a patient with “Multiple Sclerosis” based on minimal criteria alone, especially if atypical features are present. The term “Clinically Isolated Syndrome” (CIS) may remain more appropriate until the serological status is confirmed.
Conclusion
The study by Deschamps et al. serves as a vital reminder that diagnostic criteria are tools for guidance, not absolute truths. As we move toward more inclusive criteria for multiple sclerosis, the responsibility of the clinician to perform a rigorous differential diagnosis increases. In the context of inaugural optic neuritis, the 24% prevalence of AQP4 and MOG antibodies among those meeting minimal MS criteria is too high to ignore. Systematic antibody screening and meticulous interpretation of orbital imaging are no longer optional—they are foundational to evidence-based neuro-immunological care.
References
1. Deschamps R, Papeix C, Demortiere S, et al. Frequency of AQP4 and MOG Antibodies in Patients With Optic Neuritis Fulfilling Minimal New Multiple Sclerosis MRI Criteria. Neurology. 2026;106(7):e214753. PMID: 41843863.
2. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.
3. Jarius S, Paul F, Weinshenker BG, et al. Neuromyelitis optica spectrum disorders. Nat Rev Dis Primers. 2020;6(1):85.
4. Marignier R, Hacohen Y, Cobo-Calvo A, et al. Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD): a review of clinical and aetiological features. Lancet Neurol. 2021;20(9):762-772.
