Childhood-Onset Multiple Sclerosis With Progressive Dementia and Pathological Cortical Demyelination

Bunyan, Reem F.; Popescu, Bogdan F. Gh.; Carter, Jonathan L.; Caselli, Richard J.; Parisi, Joseph E.; Lucchinetti, Claudia F.

doi:10.1001/archneurol.2011.50

Cited by 12 publications

(6 citation statements)

References 11 publications

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“…White matter is primarily composed of nerve axons and myelinating oligodendrocytes and white matter lesions delineate regional destruction of myelin, oligodendrocytes and nerve axons. Although white matter plaques are considered a hallmark of MS [27], there is increasing evidence that damage to the cortical gray matter also greatly contributes to disease pathogenesis [28–35]. The gray matter is comprised of the less myelinated nerve cell bodies and dendrites, glial cells, and many capillaries.…”

Section: Overview Of Multiple Sclerosis (Ms)mentioning

confidence: 99%

The meninges: new therapeutic targets for multiple sclerosis

Russi

Brown

2015

Translational Research

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The CNS is largely comprised of non-regenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an “immune specialized” status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). In this review, we highlight the role of the meninges, tissues that surround and protect the CNS and enclose the cerebral spinal fluid, in promoting chronic inflammation that leads to neuronal damage. Although the meninges have traditionally been considered structures that provide physical protection for the brain and spinal cord, new data has established these tissues as sites of active immunity. It has been hypothesized that the meninges are important players in normal immunosurveillance of the CNS but also serve as initial sites of anti-myelin immune responses. The resulting robust meningeal inflammation elicits loss of localized blood barrier integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting of the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the blood brain barrier. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments.

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Section: Overview Of Multiple Sclerosis (Ms)mentioning

confidence: 99%

The meninges: new therapeutic targets for multiple sclerosis

Russi

Brown

2015

Translational Research

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“…How to classify a cortical lesion involving the whole grey matter width as well as a considerable region of the subadjacent white matter becomes even more complicated, and, theoretically, any of the following possibilities is feasible: a subpial lesion that extends into the white matter; a white matter lesions that extends into the cortex eventually reaching the pia; the coalescence of a subpial lesion with a white matter lesion; or the coalescence of a subpial lesion with a leukocortical lesion. While sometimes there are pathological cues that help in inferring the evolution of such a lesion [ 28 ], it is clear in most cases that its dynamics cannot be deduced from only one snapshot in the lesion's development that pathology offers.…”

Section: Classificationmentioning

confidence: 99%

Meningeal and cortical grey matter pathology in multiple sclerosis

2012

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Although historically considered a disease primarily affecting the white matter of the central nervous system, recent pathological and imaging studies have established that cortical demyelination is common in multiple sclerosis and more extensive than previously appreciated. Subpial, intracortical and leukocortical lesions are the three cortical lesion types described in the cerebral and cerebellar cortices of patients with multiple sclerosis. Cortical demyelination may be the pathological substrate of progression, and an important pathologic correlate of irreversible disability, epilepsy and cognitive impairment. Cortical lesions of chronic progressive multiple sclerosis patients are characterized by a dominant effector cell population of microglia, by the absence of macrophagic and leukocytic inflammatory infiltrates, and may be driven in part by organized meningeal inflammatory infiltrates. Cortical demyelination is also present and common in early MS, is topographically associated with prominent meningeal inflammation and may even precede the appearance of classic white matter plaques in some MS patients. However, the pathology of early cortical lesions is different than that of chronic MS in the sense that early cortical lesions are highly inflammatory, suggesting that neurodegeneration in MS occurs on an inflammatory background and raising interesting questions regarding the role of cortical demyelination and meningeal inflammation in initiating and perpetuating the disease process in early MS.

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“…The little inflammation that is present is variable depending on the type of cortical lesion. Lesions that extend through the white matter and cortex (type I) and deep cortical lesions have higher counts of inflammatory cells than those that are exclusively intracortical [ 29 , 30 ], but both have significantly less inflammation than those of white matter from the same brain [ 31 ]. The minor infiltrate in the cortical lesions include activated microglia, scarce myelin-laden macrophages, CD3+ T cells, CD20+ B cells, and rare CD138+ plasma cells.…”

Section: Reviewmentioning

confidence: 99%

Cortical injury in multiple sclerosis; the role of the immune system

2011

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The easily identifiable, ubiquitous demyelination and neuronal damage that occurs within the cerebral white matter of patients with multiple sclerosis (MS) has been the subject of extensive study. Accordingly, MS has historically been described as a disease of the white matter. Recently, the cerebral cortex (gray matter) of patients with MS has been recognized as an additional and major site of disease pathogenesis. This acknowledgement of cortical tissue damage is due, in part, to more powerful MRI that allows detection of such injury and to focused neuropathology-based investigations. Cortical tissue damage has been associated with inflammation that is less pronounced to that which is associated with damage in the white matter. There is, however, emerging evidence that suggests cortical damage can be closely associated with robust inflammation not only in the parenchyma, but also in the neighboring meninges. This manuscript will highlight the current knowledge of inflammation associated with cortical tissue injury. Historical literature along with contemporary work that focuses on both the absence and presence of inflammation in the cerebral cortex and in the cerebral meninges will be reviewed.

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Childhood-Onset Multiple Sclerosis With Progressive Dementia and Pathological Cortical Demyelination

Cited by 12 publications

References 11 publications

The meninges: new therapeutic targets for multiple sclerosis

The meninges: new therapeutic targets for multiple sclerosis

Meningeal and cortical grey matter pathology in multiple sclerosis

Cortical injury in multiple sclerosis; the role of the immune system

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