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Childhood-onset multiple sclerosis with progressive dementia and pathological cortical demyelination.

ABSTRACT: To describe a case of childhood-onset progressive multiple sclerosis with dementia and evidence of extensive cortical demyelination from brain biopsy specimen.Case report.Mayo Clinic, Rochester, Minnesota.A 26-year-old man with a history of behavioral changes starting at the age of 13 years followed by progressive dementia.Neurological examination, magnetic resonance imaging, cerebrospinal fluid studies, neuropsychological testing, and brain biopsy.Magnetic resonance imaging scans showed numerous T2-weighted hyperintensities throughout the central nervous system not associated with contrast enhancement. Brain biopsy specimens showed cortical and subcortical demyelination. All 3 types of cortical demyelinating lesions were observed: leukocortical, intracortical, and subpial. Lesions were associated with profound microglial activation. The patient continued to progress despite attempts to treat with multiple sclerosis disease-modifying therapies.Multiple sclerosis should be considered in the diagnosis of progressive dementia in children and young adults. Cortical demyelination may contribute to cognitive decline in patients with dementia due to multiple sclerosis.

SUBMITTER: Bunyan RF

PROVIDER: S-EPMC3077570 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Childhood-onset multiple sclerosis with progressive dementia and pathological cortical demyelination.

Bunyan Reem F RF Popescu Bogdan F Gh BF Carter Jonathan L JL Caselli Richard J RJ Parisi Joseph E JE Lucchinetti Claudia F CF

Archives of neurology 20110401 4

<h4>Objective</h4>To describe a case of childhood-onset progressive multiple sclerosis with dementia and evidence of extensive cortical demyelination from brain biopsy specimen.<h4>Design</h4>Case report.<h4>Setting</h4>Mayo Clinic, Rochester, Minnesota.<h4>Patient</h4>A 26-year-old man with a history of behavioral changes starting at the age of 13 years followed by progressive dementia.<h4>Interventions</h4>Neurological examination, magnetic resonance imaging, cerebrospinal fluid studies, neuro ...[more]

PMID: 21482934

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Project description:Cortical disease has emerged as a critical aspect of the pathogenesis of multiple sclerosis, being associated with disease progression and cognitive impairment. Most studies of cortical lesions have focused on autopsy findings in patients with long-standing, chronic, progressive multiple sclerosis, and the noninflammatory nature of these lesions has been emphasized. Magnetic resonance imaging studies indicate that cortical damage occurs early in the disease.We evaluated the prevalence and character of demyelinating cortical lesions in patients with multiple sclerosis. Cortical tissues were obtained in passing during biopsy sampling of white-matter lesions. In most cases, biopsy was done with the use of stereotactic procedures to diagnose suspected tumors. Patients with sufficient cortex (138 of 563 patients screened) were evaluated for cortical demyelination. Using immunohistochemistry, we characterized cortical lesions with respect to demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and a topographic association between cortical demyelination and meningeal inflammation. Diagnoses were ascertained in a subgroup of 77 patients (56%) at the last follow-up visit (at a median of 3.5 years).Cortical demyelination was present in 53 patients (38%) (104 lesions and 222 tissue blocks) and was absent in 85 patients (121 tissue blocks). Twenty-five patients with cortical demyelination had definite multiple sclerosis (81% of 31 patients who underwent long-term follow-up), as did 33 patients without cortical demyelination (72% of 46 patients who underwent long-term follow-up). In representative tissues, 58 of 71 lesions (82%) showed CD3+ T-cell infiltrates, and 32 of 78 lesions (41%) showed macrophage-associated demyelination. Meningeal inflammation was topographically associated with cortical demyelination in patients who had sufficient meningeal tissue for study.In this cohort of patients with early-stage multiple sclerosis, cortical demyelinating lesions were frequent, inflammatory, and strongly associated with meningeal inflammation. (Funded by the National Multiple Sclerosis Society and the National Institutes of Health.).

Project description:The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

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Childhood-onset multiple sclerosis with progressive dementia and pathological cortical demyelination.

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Childhood-onset multiple sclerosis with progressive dementia and pathological cortical demyelination.

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