The research, published in the Journal of Neurology by a team at the Mayo Clinic led by Purnashree Chowdhury and B. Mark Keegan, retrospectively reviewed patients seen at the Mayo MS Clinic between 2002 and 2025. The investigators searched for people with progressive central nervous system demyelinating disease and at least one year of progressive upper motor neuron weakness that could be anatomically linked to a presumed demyelinating lesion of the cerebral white matter, the internal capsule, or the upper brainstem. Crucially, they excluded patients whose progressive weakness could be explained by lesions in the spinal cord or at the cervicomedullary junction, ensuring that the brain lesions themselves were the plausible culprit.

Out of more than two decades of clinical records, the team identified just seventeen patients who met these strict criteria. The lesions were located in the cerebral white matter in twelve cases, roughly seventy percent, in the internal capsule in three cases, about eighteen percent, and in the upper brainstem in two cases, twelve percent. Ten of the seventeen patients were female, and all were white. In thirteen patients, or seventy-six percent, the progressive course began from disease onset, while in four patients, twenty-four percent, progression emerged after an initial relapsing course. The median age at the onset of progressive motor impairment was forty-six years, with an interquartile range of thirty-eight to fifty-two.

The clinical picture that emerged was strikingly consistent. Sixteen of the seventeen patients, ninety-four percent, developed progressive spastic hemiparesis, a gradual stiffening and weakening of one side of the body, while a single patient developed monoparesis, weakness confined to one limb. This pattern makes anatomical sense: the corticospinal fibers that serve the arm and leg on one side of the body travel together in a compact bundle as they descend through the subcortical white matter, the posterior limb of the internal capsule, and the cerebral peduncles of the midbrain. A demyelinating lesion that strikes this narrow corridor disrupts a large volume of motor output despite occupying a relatively small amount of tissue.

Disability at the last evaluation was substantial. The median Expanded Disability Status Scale score, the standard metric used in multiple sclerosis research, was 5.5, with an interquartile range of 4.0 to 5.5. A score of 5.5 typically corresponds to difficulty walking without aid or rest over limited distances, underscoring how much functional impact a single, well-placed brain lesion can exert when it sits astride the corticospinal tract. The findings reinforce a concept the Mayo group has been developing for years: that in some patients with progressive demyelinating disease, disability accrues not diffusely but through a small number of lesions in anatomically critical locations.

Beyond the motor system, the study documented additional neurological consequences in patients whose critical lesions lay in the cerebral white matter. Cognitive impairment occurred in six of twelve such patients, fifty percent, and seizures occurred in three of twelve, twenty-five percent. These associations suggest that large or strategically placed subcortical demyelinating lesions can affect cortical and network function beyond pure motor control, a reminder that white matter lesions are rarely as silent as their location in non-eloquent-appearing regions might imply.

Supporting laboratory and pathological data added further weight to the diagnosis. Abnormal intrathecal production of immunoglobulin G, the hallmark oligoclonal band pattern consistent with multiple sclerosis, was present in ten of fifteen patients in whom cerebrospinal fluid markers were assessed, sixty-six percent. When tissue was available, the evidence was even more direct: neuropathology confirmed demyelination in four of six biopsy specimens. These findings help distinguish the syndrome from mimics such as primary lateral sclerosis, motor neuron disease, or slow-growing gliomas, which can present with similarly gradual, one-sided spastic weakness.

The study builds on a lineage of Mayo Clinic work that has progressively mapped the anatomy of critical demyelination. Earlier investigations described progressive motor impairment arising from critical lesions of the spinal cord and the cervicomedullary junction, and a prior study identified unilateral motor progression in multiple sclerosis associated with a critical corticospinal tract lesion. Related work on progressive solitary sclerosis, in which gradual motor impairment stems from a single central nervous system demyelinating lesion, and on tumefactive demyelination, where large lesion-like areas of demyelination can trigger Wallerian degeneration of the corticospinal tract, laid the conceptual groundwork. The present study extends this framework into the intracerebral white matter itself, completing a picture in which nearly any segment of the motor pathway, from the subcortical radiations to the cord, can host a lesion capable of driving relentless progression.

Why would a single demyelinating lesion produce progressive rather than static disability? Several mechanisms are plausible and are actively debated in the progression literature. Demyelination impairs saltatory conduction, forcing action potentials to travel slowly and unreliably along denuded axons. Over time, chronic demyelination can lead to axonal degeneration, and injury to axons at one level can trigger Wallerian degeneration of the fibers downstream, so that the functional deficit grows even if the visible lesion does not. There is also the concept of functional reserve: as long as enough parallel fibers remain intact, the nervous system compensates, but progressive loss of a critical tract gradually exhausts that reserve and clinical worsening becomes apparent. The clinico-radiological paradox, the well-known mismatch between lesion burden on magnetic resonance imaging and disability, is in part resolved by recognizing that location matters as much as load.

For clinicians, the practical message is one of vigilance. A patient with a demyelinating disease who develops slowly progressive, one-sided spastic weakness deserves careful scrutiny of the entire corticospinal pathway, not only the spinal cord. Advanced magnetic resonance imaging, including tract-specific sequences, can help identify lesions along the intracerebral corticospinal tracts, and cerebrospinal fluid studies and, in selected diagnostic uncertainty, biopsy can confirm the demyelinating nature of the process. Recognizing these rare intracerebral critical lesions may spare patients unnecessary treatments for misdiagnosed motor neuron disease and may sharpen the anatomical reasoning that guides prognosis. As the Mayo team concludes, intracerebral critical demyelinating lesions associated with progressive motor impairment can rarely occur along the corticospinal tracts of the brain, and knowing where to look is the first step toward seeing them.

Subject of Research: Intracerebral critical demyelinating lesions of the corticospinal tract causing progressive motor impairment in multiple sclerosis

Article Title: Progressive motor impairment from intracerebral critical demyelinating lesions

Article References: Chowdhury, P., Flanagan, E. P., Guo, Y., Tobin, W. O., Coen, B. A., Lucchinetti, C. F., Weinshenker, B. G., Kantarci, O. H., & Keegan, B. M. (2026). Progressive motor impairment from intracerebral critical demyelinating lesions. Journal of Neurology, 273(10), Article 629. https://doi.org/10.1007/s00415-026-14168-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14168-3

Keywords: multiple sclerosis, demyelinating disease, corticospinal tract, critical lesion, progressive motor impairment, spastic hemiparesis, internal capsule, cerebral white matter, Expanded Disability Status Scale, cervicomedullary junction, neurology, Wallerian degeneration

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 research team, led by investigators at Baylor College of Medicine and Texas Children’s Hospital, reviewed the medical records of all pediatric patients diagnosed with MOGAD at their institution between January 2017 and December 2024. To be included, patients had to experience a core clinical demyelinating event and test positive for MOG-IgG antibodies on clinical cell-based assays, with either a clear positive titer of at least 1:100 or a low-positive titer supported by consistent clinical or magnetic resonance imaging features, in line with the international consensus diagnostic criteria established in 2023. Patients with isolated optic neuritis were excluded from the comparison group because their disease course differs fundamentally from other phenotypes and rarely involves seizures, hydrocephalus, or intracranial hypertension.

Of the 124 pediatric patients with MOGAD identified during the eight-year window, 37 required admission to the pediatric intensive care unit, driven by altered mental status, seizures, or the rapid onset of weakness. Sixteen of these critically ill children had to be intubated because of altered consciousness or seizures, with a median duration of mechanical ventilation of three days. Fever was strikingly common in the ICU group, present in 24 of the 37 patients, and cerebrospinal fluid white blood cell counts were significantly higher among those admitted to intensive care compared with those managed on general wards. The ICU cohort also skewed male, and children with the cerebral cortical encephalitis phenotype were dramatically overrepresented, accounting for nearly a third of ICU admissions compared with under five percent of non-ICU cases.

Perhaps the most consequential finding concerns intracranial pressure. Twelve patients showed neuroimaging evidence of increased intracranial pressure, including four with signs of herniation or cerebral shift, five with optic nerve head protrusion and posterior globe flattening in the absence of clinical optic neuritis, and others with sulcal effacement. When the investigators combined imaging evidence, elevated opening pressures on lumbar puncture, and the use of hyperosmolar therapy, they identified 16 unique patients, more than 40 percent of the ICU cohort, with evidence of elevated intracranial pressure. Seven children received hyperosmolar therapy with hypertonic saline, and two underwent placement of invasive intracranial pressure monitoring devices, one of which recorded pressures as high as 50 millimeters of mercury and remained in place for 14 days to guide pharmacologic treatment.

Seizures were another dominant feature of critical MOGAD. Eighteen of the 37 ICU patients experienced seizures, and eleven developed status epilepticus, including one child who met criteria for new-onset refractory status epilepticus, a life-threatening form that resists standard antiseizure medications. Notably, five patients had electrographic seizures visible only on continuous electroencephalography, with no clinical correlate, and all five carried the cerebral cortical encephalitis phenotype. Twenty-seven patients underwent continuous EEG monitoring, revealing a heterogeneous mix of background abnormalities, focal slowing, interictal epileptiform discharges, and rhythmic and periodic patterns on the ictal-interictal continuum, including lateralized and generalized periodic discharges and rhythmic delta activity with and without superimposed spikes. Importantly, the authors found no specific EEG biomarker that reliably distinguishes MOGAD from other autoimmune encephalopathies, contradicting earlier suggestions that the anterior temporal lobe is spared from ictal activity in this disease.

Treatment patterns in the cohort reflected both the promise and the uncertainty of current immunotherapy practice. Most children, 32 of the 37, received immunotherapy during their ICU stay, with intravenous methylprednisolone as the standard first-line agent, alone in 26 cases and combined with intravenous immunoglobulin or plasmapheresis in others. Thirteen patients were adequately treated with first-line therapy, but the remaining nineteen required escalation, most commonly to plasmapheresis or intravenous immunoglobulin, with a median time to escalation of three days. One severely affected child with markedly elevated interleukin-6 levels received the IL-6 receptor antagonist tocilizumab after failing steroids, plasmapheresis, and immunoglobulin, and another received intrathecal dexamethasone. The authors argue that in life-threatening presentations, clinicians should consider early dual immunotherapy, and that emerging data on IL-6 receptor blockade may justify earlier use of tocilizumab in refractory cases.

The study also exposes a diagnostic trap that carries real consequences. Five ICU patients initially received no immunotherapy because their fever and elevated cerebrospinal fluid white cell counts led clinicians to suspect viral encephalitis. Although all five appeared to return to their neurologic baseline without intervention, three later deteriorated and required readmission with new neurologic symptoms before finally receiving immunotherapy. The authors emphasize that fever and cerebrospinal fluid pleocytosis, typically associated with infection, frequently accompany MOGAD attacks and may simply reflect the intensity of neuroinflammation. Their recommendation is that when MOGAD is suspected in a critically ill child, high-dose intravenous steroids should not be delayed while infectious workups proceed in parallel, with infectious disease specialists involved to help weigh the risks.

Outcomes data underscore the stakes of getting this right. Children admitted to the ICU had significantly worse scores on the Functional Status Scale and the Pediatric Cerebral Performance Category scale at follow-up than those managed outside the ICU, were far more likely to require inpatient rehabilitation, and were more than six times as likely to be diagnosed with epilepsy later in life. Intriguingly, the risk of future epilepsy did not correlate with whether a child had seizures or even status epilepticus during the acute illness. Instead, it tracked with evidence of elevated intracranial pressure: 71 percent of children who went on to develop epilepsy had clinical or imaging concern for raised intracranial pressure, compared with just 15.5 percent of those who did not. The authors speculate that secondary cerebral injury, including encephalomalacia and cortical laminar necrosis visible on follow-up MRI, may create the substrate for epileptogenesis, making intracranial hypertension a modifiable target for preventing long-term harm.

The study is not without limitations. Its retrospective design means the clinical approach to assessing and treating intracranial pressure was not standardized, and the authors acknowledge that many patients with evidence of raised pressure did not receive pressure-directed therapy, possibly because the complication was underrecognized in the setting of autoimmune cerebral inflammation. The single-center, tertiary-quaternary referral setting also introduces referral bias. Still, the investigators argue that the findings make a compelling case for systematic neuromonitoring in critically ill children with MOGAD, including routine measurement of opening pressure during lumbar puncture, cautious use of fundoscopy, which proved insensitive in this cohort, and greater adoption of transcranial doppler ultrasonography, which showed elevated middle cerebral artery velocities suggestive of early hyperemia in the four patients tested. They call for early multidisciplinary involvement spanning critical care, neurocritical care, neurosurgery, and infectious disease, and for prospective studies to determine whether aggressive, standardized management of seizures and intracranial pressure can improve the long-term outlook for these children.

Subject of Research: Critical illness, seizures, and intracranial hypertension in pediatric MOG antibody disease requiring intensive care

Article Title: Pediatric MOGAD in the Intensive Care Unit: A Case Series

Article References: Runco, A. D., Davila-Williams, D., Moeller, K. K., Sandweiss, A. J., Ballinger, E., Shukla, N., Riviello, J. J., Erklauer, J. C., & Fisher, K. S. (2026). Pediatric MOGAD in the Intensive Care Unit: A Case Series. Neurocritical Care. https://doi.org/10.1007/s12028-026-02653-6

Image Credits: AI Generated

DOI: 10.1007/s12028-026-02653-6

Keywords: MOGAD, pediatric neurology, neurocritical care, intracranial pressure, status epilepticus, demyelinating disease, continuous EEG, immunotherapy, cerebral cortical encephalitis, ADEM, epilepsy risk, intensive care