The research, led by Luca Bollo and Angela Vidal-Jordana at the Multiple Sclerosis Centre of Catalonia in collaboration with Vall d’Hebron University Hospital and published in the Journal of Neurology, prospectively followed 46 patients experiencing their first episode of unilateral subacute optic neuritis. Each participant underwent a comprehensive workup: detailed clinical examination, orbital and brain magnetic resonance imaging, optical coherence tomography of the retinal nerve fiber layer, laboratory testing including serum antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein, and visual evoked potentials, a neurophysiological test that measures how efficiently the visual pathway conducts signals from the retina to the visual cortex. The investigators then applied the original ICON 2022 criteria and compared the results with two modified versions of the framework.

The headline finding is stark. Under the original ICON 2022 criteria, only 20 of the 46 patients, or 43.5 percent, reached the category of definite optic neuritis. When the researchers loosened the clinical requirements, allowing a diagnosis with incomplete clinical features, and required two abnormal paraclinical tests among MRI, optical coherence tomography, and laboratory findings, the proportion of definite cases rose to 32 patients, or 69.6 percent, a difference that was highly statistically significant. When visual evoked potentials were added to the paraclinical toolkit alongside the less stringent clinical definitions, the figure climbed further still, to 39 patients, or 84.8 percent, nearly double the yield of the original criteria.

To understand why this matters, it helps to unpack what each test actually measures. Magnetic resonance imaging with orbital sequences can reveal T2-hyperintense signal and gadolinium enhancement along the optic nerve, direct evidence of inflammation and blood-nerve barrier disruption. Optical coherence tomography quantifies the thickness of the retinal nerve fiber layer and the ganglion cell complex, detecting the axonal loss that follows an inflammatory attack. Visual evoked potentials, by contrast, probe function rather than structure: a flashing or pattern-reversing checkerboard stimulus is presented to each eye while electrodes over the occipital cortex record the timing and amplitude of the brain’s response. Demyelination delays the P100 latency, the characteristic peak of the response, often before structural thinning becomes measurable on scans.

This functional sensitivity is precisely why the addition of VEPs proved so powerful in the study. Patients with incomplete clinical presentations, for example those without the classic combination of pain, visual acuity loss, color vision impairment, and a relative afferent pupillary defect, could still be classified as definite optic neuritis when their paraclinical workup was typical. The effect was most pronounced in exactly this subgroup: individuals whose symptoms did not tick every clinical box but whose MRI, OCT, and electrophysiology told an unambiguous story of optic nerve inflammation. In clinical terms, the modified criteria rescued a substantial fraction of patients who would otherwise have been left in diagnostic limbo, a category with real consequences for treatment decisions, follow-up intensity, and counseling about the risk of future demyelinating events such as multiple sclerosis.

The Barcelona group’s work does not stand in isolation. Since the ICON criteria appeared in The Lancet Neurology in 2022, several groups have tested them against independent cohorts and reported similar concerns about stringency. Correspondence in the same journal questioned how the criteria performed in atypical presentations, and the Acute Optic Neuritis Network published an application of the criteria in 2024 that highlighted classification gaps. Meanwhile, the field of demyelinating disease diagnostics has been moving rapidly toward incorporating the optic nerve more broadly. The 2024 revisions of the McDonald criteria for multiple sclerosis, the most consequential diagnostic framework in the field, now allow optic nerve involvement, demonstrated by MRI or by visual evoked potentials, to contribute to the demonstration of dissemination in space, a change that formally elevates VEPs from a niche neurophysiological tool to a first-line diagnostic instrument.

Against that backdrop, the new study offers prospective, patient-level evidence that the optic neuritis criteria should evolve in the same direction. The authors’ proposed modification is conceptually simple: rather than demanding a complete clinical syndrome, the framework would accept a less strict clinical category and then require corroboration from two abnormal paraclinical tests, with VEPs counted alongside MRI, OCT, and serology. This modular architecture mirrors how modern neurology increasingly thinks about diagnosis, as a Bayesian exercise in which each test contributes independent information about the probability of disease. A delayed P100 latency on VEPs carries information that is partly independent of a normal-appearing retinal nerve fiber layer on OCT, and both can be informative when the MRI shows only subtle optic nerve signal change.

There are important caveats. The cohort of 46 patients is modest, and all participants were recruited at specialized centers in Catalonia with access to expert neuroradiology, neuro-ophthalmology, and neurophysiology, so the modified criteria will need validation in larger and more diverse populations, including settings where antibody testing and VEP recording are less readily available. The study also focused on first-episode unilateral optic neuritis, leaving open the question of how the modified framework performs in bilateral, recurrent, or pediatric disease, where differential diagnoses such as neuromyelitis optica spectrum disorder and MOG antibody-associated disease loom larger and where serological markers carry decisive weight. The researchers themselves frame their findings as supporting revisions aimed at broader clinical applicability rather than as a finished replacement for the 2022 consensus.

Even so, the implications for patients are tangible. A person who wakes with a sore, blurry eye but whose examination findings are incomplete currently risks being labeled with uncertain optic neuropathy, delaying disease-modifying therapy if multiple sclerosis is the underlying cause, or delaying plasma exchange and immunosuppression if aquaporin-4 antibody disease is suspected. By formally recognizing that paraclinical evidence, especially electrophysiological evidence from visual evoked potentials, can compensate for an atypical clinical picture, the modified criteria promise faster, more confident classification and, downstream, better-targeted treatment. The study was funded by the Instituto de Salud Carlos III, and its datasets are available from the corresponding authors, an invitation for other centers to stress-test the approach.

The broader lesson reaches beyond one disease. Diagnostic criteria in neurology have historically leaned heavily on clinical acumen, with imaging and laboratory tests playing supporting roles. The trajectory now visible across multiple sclerosis, neuromyelitis optica, MOG antibody disease, and optic neuritis points toward criteria that fuse clinical features with structural imaging, retinal layer quantification, serology, and neurophysiology in a single probabilistic framework. The Barcelona study demonstrates concretely what that fusion can achieve: the proportion of patients confidently classified as having definite optic neuritis nearly doubled, from 43.5 to 84.8 percent, simply by trusting the objective signals that modern technology can already deliver. If subsequent multicenter validation confirms these results, the humble visual evoked potential, a test first described decades ago, may finally take its place at the center of optic nerve diagnostics, and fewer patients will be left waiting in the gray zone between suspicion and certainty.

Subject of Research: Prospective evaluation of the 2022 international consensus criteria for optic neuritis and the diagnostic value of visual evoked potentials

Article Title: Evaluation of the 2022 international consensus criteria for optic neuritis: the role of clinical features and visual evoked potentials

Article References: Bollo, L., Vidal-Jordana, A., Rodríguez-Acevedo, B., Sceppacuercia, S., Mongay-Ochoa, N., Zancan, V., Ajdinaj, P., Braga, N., Cabello, S., Alberich, M., Corral, J., Auger, C., Tintoré, M., Montalban, X., Pareto, D., Moncho, D., Rovira, À., & Sastre-Garriga, J. (2026). Evaluation of the 2022 international consensus criteria for optic neuritis: the role of clinical features and visual evoked potentials. Journal of Neurology, 273(10), Article 561. https://doi.org/10.1007/s00415-026-13972-1

Image Credits: AI Generated

DOI: 10.1007/s00415-026-13972-1

Keywords: optic neuritis, diagnostic criteria, visual evoked potentials, ICON criteria, MRI, optical coherence tomography, multiple sclerosis, demyelination, neurology, optic nerve, MOG antibodies, prospective study

The need for such guidance is rooted in biology. AQP4+ NMOSD and MOGAD are antibody-mediated inflammatory conditions of the central nervous system, but they differ fundamentally in their immunopathology. AQP4 antibodies target a water channel concentrated on astrocytic endfeet, producing lesions that cluster around the ventricles, in the area postrema, and along regions of high aquaporin 4 expression. MOG antibodies, by contrast, attack a myelin surface protein, generating a distinct pattern of demyelination that often involves the optic nerves, spinal cord and, in children, the cerebral cortex. These differences translate into different imaging signatures, different disease courses and different treatment strategies, making accurate radiological interpretation a matter of clinical urgency.

Yet the panel acknowledges that the diagnostic landscape remains treacherous. Imaging features of the two diseases overlap with each other and with multiple sclerosis, lesions evolve in unpredictable ways over time, and acquisition protocols vary widely between centers. A patient presenting with optic neuritis or transverse myelitis may harbor any of these conditions, and the wrong diagnosis can lead to the wrong therapy, with potentially devastating consequences. The new recommendations therefore serve a dual purpose: standardizing practice and sharpening the differential diagnosis at the bedside.

At the heart of the document are standardized protocols. The authors define a core set of MRI sequences that should be performed in every patient, alongside optional sequences for specific clinical questions. Brain MRI, spinal cord imaging and orbital imaging each receive detailed attention, with guidance on the timing of scans at presentation, during acute attacks, and in the follow-up period. The recommendations extend the MAGNIMS framework, long established for multiple sclerosis, into these antibody-mediated diseases, creating a parallel infrastructure for image acquisition and reporting that can be implemented in routine clinical practice.

The characteristic conventional MRI findings of each disease receive careful treatment. In AQP4+ NMOSD, lesions typically affect the spinal cord over long segments, the area postrema causing intractable hiccups and nausea, periependymal surfaces of the ventricles, and the optic chiasm. In MOGAD, longitudinally extensive myelitis is also common but tends to involve the conus medullaris, while optic nerve involvement is frequently anterior and bilateral, and cortical lesions with seizures, including the FLAMES pattern of unilateral cortical FLAIR hyperintensity, point toward MOG antibodies. Recognizing these patterns helps clinicians distinguish the two diseases from each other and from multiple sclerosis, where short-segment cord lesions, central vein signs and paramagnetic rim lesions dominate.

One of the most clinically valuable sections addresses the acute attack. MRI plays a decisive role in determining whether a patient is experiencing a true relapse or a pseudo-relapse, a distinction that changes management entirely. The panel also highlights the phenomenon of radiologic lag in MOGAD, in which brain lesions may appear or evolve days to weeks after the clinical onset of an attack, meaning an early normal scan does not exclude active disease. Serial imaging during the attack window can therefore reveal lesion dynamics that a single time point misses, and the timing of follow-up scans matters as much as their content.

Post-attack recovery is another area where the recommendations break new ground. MOGAD lesions, unlike those of many other demyelinating diseases, have a striking tendency to resolve on T2-weighted images, and the panel discusses the timing and predictors of this lesion resolution. The degree of tissue recovery, visible as the fading of lesions and the relative preservation of tissue volume, carries prognostic weight and informs decisions about how aggressively to treat and how long to continue immunotherapy. Spinal cord atrophy, which correlates with disability in NMOSD, is identified as a key longitudinal measure.

Beyond conventional imaging, the document surveys the added value of non-conventional MRI techniques. Diffusion-based measures, myelin-sensitive sequences, magnetization transfer imaging and volumetric analysis can probe microstructural damage, inflammatory activity and tissue repair that standard T2 and T1 sequences cannot capture. Advanced approaches such as neurite orientation dispersion and density imaging, 7 Tesla imaging of myelin signal in normal-appearing white matter, and even indices of glymphatic system dysfunction are reviewed as research tools that may mature into clinical biomarkers. The panel also points to the emerging role of machine learning and radiomics, including deep learning models trained to distinguish MOGAD from multiple sclerosis, as a frontier for automated diagnostic support.

The recommendations confront one of the field’s most stubborn problems: seronegative NMOSD. Patients who present with the clinical and radiological phenotype of NMOSD but lack detectable AQP4 antibodies form a heterogeneous group whose classification remains uncertain, and whose response to therapy may differ from that of seropositive patients. The panel outlines the diagnostic complexity of this population and argues that novel imaging biomarkers are needed to improve classification and treatment precision, potentially allowing MRI itself to stratify patients when antibody testing is inconclusive.

Ultimately, the consensus document represents a maturing of the field. With targeted therapies now available for both AQP4+ NMOSD and MOGAD, and with growing interest in when immunotherapy can be safely discontinued, standardized imaging is no longer a luxury but a clinical necessity. By codifying what to scan, when to scan and how to interpret the results, the MAGNIMS panel has given neurologists, neuroradiologists and researchers a common language for these diseases, one that should accelerate both better individual care and the multicenter trials needed to push the field forward.

Subject of Research: Consensus recommendations for the use of MRI in diagnosing and monitoring neuromyelitis optica spectrum disorder and MOG antibody-associated disease

Article Title: Use of MRI in neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease — MAGNIMS consensus recommendations

Article References: Cortese, R., Hacohen, Y., Arrambide, G., Bianchi, A., DeLuca, G., Filippi, M., Gasperini, C., Geraldes, R., Granziera, C., Haider, L., Messina, S., Sastre-Garriga, J., Preziosa, P., Rocca, M. A., Rovira, A., Tintoré, M., Toosy, A., Tortorella, C., Vaneckova, M., … Schoonheim, M. (2026). Use of MRI in neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein antibody-associated disease — MAGNIMS consensus recommendations. Nature Reviews Neurology. https://doi.org/10.1038/s41582-026-01271-2

Image Credits: AI Generated

DOI: 10.1038/s41582-026-01271-2

Keywords: MRI, NMOSD, MOGAD, aquaporin-4 antibodies, myelin oligodendrocyte glycoprotein, demyelinating disease, neuroimmunology, MAGNIMS, optic neuritis, myelitis, diagnostic criteria, biomarkers

The story begins when a previously healthy five-year-old girl was referred to the neurology unit with a fixed right mydriasis, a persistently dilated pupil, and complete retinal detachment in the same eye. Notably, she had never experienced fever or eye pain, features that might otherwise have steered clinicians toward an infectious or inflammatory process of a different character. Brain magnetic resonance imaging revealed severe right optic neuritis, appearing as hyperintensity on T2-weighted sequences, and serum testing detected anti-MOG antibodies at a low titer of 1:10. On the strength of these findings, the team diagnosed MOGAD, an autoimmune condition in which antibodies target myelin oligodendrocyte glycoprotein, a protein on the surface of myelin sheaths in the central nervous system, and initiated monthly intravenous immunoglobulin at a dose of 2 grams per kilogram.

The initial treatment did not hold the disease in check. Three months later, the girl suffered a brainstem relapse marked by vomiting, dysarthria, and ataxia. Repeat MRI showed contrast-enhancing lesions in both supra- and infratentorial regions, together with tonsillar herniation and obstructive hydrocephalus, a life-threatening buildup of cerebrospinal fluid pressure that required a third ventriculocisternostomy, a surgical bypass procedure. High-dose intravenous methylprednisolone pulses of 20 milligrams per kilogram per day were administered for seven days and produced only partial improvement. Despite ongoing therapy, a further relapse followed just three months later, this time presenting with cerebellar ataxia, dysarthria, and a right foot drop. The clinical picture was that of a refractory, relentlessly relapsing inflammatory disorder of the central nervous system, and the team escalated accordingly.

Faced with this refractory-relapsing MOGAD phenotype, the clinicians turned to rituximab, a monoclonal antibody that depletes CD20-positive B cells and is increasingly used as second-line therapy in antibody-mediated neuroinflammatory disease. The drug was given at 375 milligrams per square meter of body surface area weekly for four weeks, but it was discontinued after yet another relapse. Mycophenolate mofetil at 1000 milligrams per day was then added to the monthly immunoglobulin cycles, and this combination finally produced a more stable remission lasting three years. Even during this quiescent period, however, a subtle clue persisted: the girl’s anti-MOG antibody titers fluctuated, swinging between positive and negative results. The authors emphasize precisely this point in their critique, arguing that the role of MOG-IgG serum titer changes and oscillations should not be solely used to clarify the nature of neuroinflammatory pictures in children.

The remission shattered when the girl was 9.6 years old. She abruptly developed a crossed brainstem syndrome, a pattern of neurological deficits produced by a lesion interrupting nerve tracts and cranial nerve nuclei within the brainstem, manifesting as right lower limb hypertonia, flaccid paralysis of the left arm, anarthria, or complete loss of speech, lingual akinesia, and a fixed rightward deviation of the head. A new brain MRI revealed multiple hemorrhagic lesions lined through the thalamus, the nucleo-capsular regions, and the pons. Hemorrhagic transformation within inflammatory brain lesions of this severity is distinctly unusual for typical MOGAD and signaled that the underlying process was something far more destructive than a conventional demyelinating disease.

At this critical juncture, the clinicians returned to a physical sign that had been present all along: the girl’s silvery-gray hair and eyebrows. This peculiar pigmentation, easily overlooked or attributed to benign variation in a child with an autoimmune diagnosis, is in fact the hallmark of Griscelli syndrome, a group of autosomal recessive disorders defined by partial albinism. Acting on this reassessment, the team performed a molecular testing panel for hemophagocytic lymphohistiocytosis, or HLH, a hyperinflammatory syndrome in which immune cells attack the body’s own tissues and organs, using peripheral blood mononuclear cells. The panel revealed two variants in the RAB27A gene on chromosome 15q21: c.153+5G>A, a splice site variant that alters pre-mRNA splicing, and c.514_518del, a pathogenic five-base-pair deletion.

The molecular findings confirmed Griscelli syndrome type 2, catalogued as OMIM #607623, an ultrarare condition caused by mutations in RAB27A and characterized by partial albinism together with impaired cytotoxic activity of T cells and natural killer cells, carrying a risk of life-threatening hemophagocytic lymphohistiocytosis. The biology connects the two seemingly unrelated features of the case. The Rab27a protein is essential for the release of melanin from melanocytes into surrounding cells; when it is dysfunctional, melanin accumulates abnormally within melanocytes and is not transferred properly, producing the characteristic silvery-gray hair and skin hypopigmentation. The same protein is required for the release of cytolytic granules by cytotoxic lymphocytes, so its absence leaves the immune system unable to eliminate infected or activated cells, permitting uncontrolled immune activation that can culminate in the cytokine storm of HLH.

Importantly, the authors note that HLH may be virtually absent in some patients who present with a completely neurologic phenotype, even when molecular findings are fully consistent with Griscelli syndrome type 2. This phenotypic expansion, previously described in the literature in an eleven-year-old girl with Rab27A mutations and no hemophagocytosis, helps explain why the diagnosis remained hidden for more than five years in the present case. After the genetic confirmation, the girl was started on ruxolitinib, a Janus kinase inhibitor that dampens inflammatory signaling downstream of cytokine receptors, at a dose of 5 milligrams twice daily, and she was placed on the waiting list for hematopoietic stem cell transplantation, the only curative option for this disease. Sadly, a slowly progressive multiorgan failure developed five months later, and the girl died at the age of ten.

The case carries a pointed lesson for pediatric neurologists and immunologists alike. Rare genetic errors of immunity can coexist with hypopigmentation skin disorders, and the authors urge healthcare providers to recall that dysregulated immunity may be camouflaged by devastating neuroinflammatory pictures that begin with something as common as optic neuritis. Autoimmune test results, including anti-MOG positivity, may taint the true disease identity, because a positive MOG test does not automatically mean MOGAD. Low antibody titers, atypical clinical features such as absent pain, hemorrhagic lesions, relapses refractory to appropriately escalated immunotherapy, and fluctuating serology should all prompt a broader differential diagnosis that includes inborn errors of immunity. In such patients, recognizing subtle dysmorphic or pigmentation cues and pursuing molecular panels early can redirect treatment toward targeted immunomodulation and, ultimately, curative transplantation before irreversible damage accumulates.

Published as a letter in response to Aduru and colleagues’ finding that MOGAD is the most common cause of isolated optic neuritis in children, this report does not overturn that conclusion but complicates it. It stands as a reminder that the most frequent explanation is not always the correct one, and that in medicine, as in this child’s silver-gray hair, the most visible clue to a hidden diagnosis may be the one easiest to dismiss.

Subject of Research: Griscelli syndrome type 2 masquerading as MOG antibody-associated neuroinflammatory disease in a child

Article Title: A Lethal Progressive Neuroinflammation Disguised as MOGAD Revealing a Final Diagnosis of Griscelli Syndrome

Article References: Veredice, C., Arpaia, C., Contaldo, I., Capasso, A., & Rigante, D. (2026). A Lethal Progressive Neuroinflammation Disguised as MOGAD Revealing a Final Diagnosis of Griscelli Syndrome. Annals of Clinical and Translational Neurology, 13(8), 1740-1742. https://doi.org/10.1002/acn3.70470

Image Credits: AI Generated

DOI: 10.1002/acn3.70470

Keywords: Griscelli syndrome, MOGAD, optic neuritis, RAB27A, hemophagocytic lymphohistiocytosis, neuroinflammation, pediatric neurology, anti-MOG antibodies, partial albinism, rituximab, ruxolitinob, genetic diagnosis