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Identification of Inflammatory Neuronal Injury and Prevention of Neuronal Damage in Multiple Sclerosis:  Hope for Novel Therapies?

Frauke Zipp, MD1; Ralf Gold, MD2; Heinz Wiendl, MD3
[+] Author Affiliations
1Focus Program Translational Neurosciences (FTN), Rhine Main Neuroscience Network, Department of Neurology (rmn2), University Medical Center of the Johannes-Gutenberg University Mainz, Mainz, Germany
2Department of Neurology, St Josef-Hospital/Ruhr University Bochum, Bochum, Germany
3Department of Neurology, University of Münster, Münster, Germany
JAMA Neurol. 2013;70(12):1569-1574. doi:10.1001/jamaneurol.2013.4391.
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Importance  Although multiple sclerosis (MS) has long been considered the prototype for an inflammatory, demyelinating disease of the central nervous system, modern histopathology and imaging techniques show that significant damage to neuronal structures already start occurring in the earliest stages of the disease. As the disease progresses, the extent of neuronal pathology accumulates. Therapeutic progress in terms of the prevention of increased disability has only just begun.

Objective  To review possible diagnostic improvements of neuronal compartment pathology as well as direct therapeutic interventions based on reports from the last decade and outline clinical results from studies and perspectives on the progression of MS.

Evidence Review  Literature search focused on publications and the references contained therein, relating to neuronal compartment pathology and direct therapeutic interventions published in the last decade in well-established peer-reviewed journals. The quality of the cited works was ensured by their acceptance by peer review, participation in clinical trials, and authors’ own expert assessment.

Findings  Current MS therapies as well as medications that are in late phase 3 trials or under approval exhibit primarily anti-inflammatory properties. However, clinical and imaging data demonstrate the potential of using novel therapies to prevent neuronal damage. Whether these exhibit effects on the neuronal compartment due to interference with the immune system or additional direct effects depends without question on the specific mechanism of action.

Conclusions and Relevance  Combining anti-inflammatory and direct neuroprotective, neuroregenerative/repair therapy strategies may open up new avenues in the treatment of MS.

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Figure.
Divergent Activity of the Immune and Nervous Systems

The upper triangles depict the hypothesis regarding neural and immune homeostasis in multiple sclerosis (MS). The center section of the graph contains the most frequent clinical course, using blue bars for disability and the gray shaded area for atrophy increase during the MS disease. The bottom section contains the existing understanding of inflammatory activity in imaging and pathology. The underlying proinflammatory genetic predisposition of MS has been confirmed by the work of the International Multiple Sclerosis Genetics Consortium. At the beginning of MS, the central nervous system is clearly capable of retaining its homeostasis. From an Expanded Disability Status Scale (EDSS) score of 3 to 4 onward, there seems to be a stereotypical pattern for disability increase with a lack of immune attacks.31

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