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