Elsevier

Neurologic Clinics

Volume 23, Issue 1, February 2005, Pages 107-129
Neurologic Clinics

Neuropathobiology of multiple sclerosis

https://doi.org/10.1016/j.ncl.2004.09.008Get rights and content

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Neurologic disability in multiple sclerosis

In RRMS, neurologic disability is caused by infiltrating leukocytes, edema from BBB breakdown, and demyelination (Fig. 1). The appearance of neurologic symptoms is rapid, subsiding usually within 4 to 8 weeks. Because demyelination is a slow process, initial symptoms probably result from conduction block caused by inflammation and edema (see Fig. 1B). Relapses often are preceded by increases in the number of immune cells and levels of specific cytokines in cerebrospinal fluid (CSF).

Axonal loss in multiple sclerosis

Often, axonal injury disrupts axonal transport, resulting in the accumulation of proteins and formation of axonal ovoids. When axons are transected, the proximal axonal segment still connected to the neuronal cell body survives, whereas the distal axonal segment undergoes wallerian degeneration. Anterograde transport from the neuronal perikarya continues leading to the accumulation of organelles, proteins, and a variety of other molecules at the ends of the proximal axonal segments, resulting

Immune-mediated axonal loss

Development of neuroprotective therapies is critically dependent on identifying the cellular and molecular mechanisms of axonal transection in MS and understanding the interplay of these mechanisms with disease progression. Elucidating the pathophysiology of axonal injury is complicated, because different or multiple mechanisms of axonal degeneration may occur, depending on the stage of the disease. Positive correlations between inflammatory activity of MS lesions and axonal damage suggest that

Loss of chronically demyelinated axons

Axonal loss is clinically silent early in MS because of the compensatory capacity of the CNS. Several fMRI studies indicate that compensation for axonal loss occurs by functional reorganization of the cortex [14], [15], [16], [17]. In a recent study using fMRI and MRS, patients who had RRMS with no overt permanent functional disability demonstrated a fivefold increase in sensorimotor cortex activation with simple hand movements compared with individuals who did not have MS [14]. Once axonal

Pathology of cortical multiple sclerosis lesions

Demyelination also occurs in the gray matter of patients who have MS [83], [84], [85], [86], [87]. Little is known about the impact of cortical pathology on neurologic disability in MS. A recent study detected axonal transection, dendritic transection, and neuronal apoptosis in cortical MS lesions [86]. The incidence of cerebral cortical lesions in MS is described in several studies. Brownell and Hughes report that 26% of the brain lesions in MS involve the gray matter [83]. Approximately 65%

Decreased inflammation in cortical lesions

The number of inflammatory cells in Type I cortical lesions is significantly less than in white matter lesions [86]. The cortical part of Type I lesions contains 6 times fewer CD68-positive microglia/macrophages and 13 times fewer CD3-positive lymphocytes than the white matter part of the lesions. Reduced inflammatory cells in Type I and Type II cortical lesions compared with white matter lesions has been described [91]. In cortical lesions, perivascular cuffing was rare and, when present,

Neuronal damage in cortical lesions

Transected axons, transected dendrites, and neuronal apoptosis were identified in cortical lesions from patients who had MS whose clinical disease ranged from 2 weeks to 27 years [86]. Substantial neuronal injury occured in cortical lesions despite reduced cortical inflammation. Neurofilament-positive swellings were detected along dendrites and axons, suggesting disruption of normal cellular transport. Confocal analysis identified many of these swellings as the terminal ends of axons and

Microglial targeting of neurons in cortical multiple sclerosis lesions

Microglia are the resident macrophages of the CNS responsible for monitoring pathologic changes [105], [106]. In cortical MS lesions, microglia are detected closely associated with neurons [86]. Elongated microglia are oriented perpendicular to the pial surface, closely apposed, and ensheathing apical dendrites and axons in active and chronic active cortical lesions (see Fig. 5C, D). In addition, other highly ramified stellate-shaped microglia often extend processes to neuronal perikarya and

Contribution of cortical lesions to neurologic disability in multiple sclerosis

The studies described previously implicate cortical lesions as major contributors to disease burden in patients who have MS. Neuronal damage in motor and sensory cortex certainly has an impact on ambulatory decline in patients who have MS. In addition to motor and sensory deficits, 40% to 70% of all individuals diagnosed with MS experience various cognitive deficits [114], [115]. Cognitive functions commonly affected include learning, memory, and information processing [114]. A positron

Functional consequences

The concept of MS as an inflammatory demyelinating and neurodegenerative disease provides a conceptual framework that explains disease progression and development of permanent neurologic disability in patients who have MS (Fig. 6). The time from clinical disease onset of MS to a score of 4 on the EDSS ranges from 1 to 33 years; however, once patients reach EDSS 4, the time to EDSS 7 is similar among the patients [117]. These observations suggest an initiation of a cascade of neuronal

Summary

Neuronal injury is an integral part of MS. Loss of axons, dendrites, and neurons contribute to the irreversible permanent neurologic disability experienced by patients who have MS. Various aspects and potential mechanisms of neuronal injury in MS recently have been described. A multidisciplinary approach and a variety of animal models have increased understanding of the neuropathologic mechanisms involved in the development of permanent neurologic disability. Several lines of evidence indicate

Acknowledgments

The authors thank Susan De Stefano for assistance with preparation of the manuscript and Dr. Grahame Kidd and Rosalia Yacubova for assistance with the figures.

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    This work was supported by grant no. NS35058 from the National Institutes of Health.

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