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Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis

From Buffalo Neuroimaging Analysis Center (R.Z., M.G.D.), The Jacobs Neurological Institute, Department of Neurology, State University of New York, Buffalo; Department of Neurology (A.T.R.), University of Chicago, IL; Neuroimaging Research Unit (M.F.), Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy; Department of Neurology (A.M.), Louisiana State University Health Sciences Center, Shreveport; Neurology Section (O.S.), VA North Texas Health Care System, Medical Service, Dallas, TX; Center for Brain Research (H.L.), Medical University of Vienna, Wien, Austria; Department of Neurology (M.K.R.), The Ohio State University, Columbus; Departments of Neurology and Ophthalmology (E.M.F.), University of Texas Southwestern Medical Center at Dallas; and Department of Neurology (O.K.), Multiple Sclerosis Center, Wayne State University School of Medicine, Detroit, MI.

Address correspondence and reprint requests to Dr. Robert Zivadinov, Buffalo Neuroimaging Analysis Center, Jacobs Neurological Institute, 100 High Street, Buffalo, NY 14203 rzivadinov{at}thejni.org

Disease-modifying agents (DMAs), including interferon beta (IFNβ) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNβ administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNβ demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non–tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Abbreviations: AHSCT = autologous hematopoietic stem cell transplantation; BBB = blood–brain barrier; BV = brain volume; CIS = clinically isolated syndrome; DB = double-blind; DMAs = disease-modifying agents; GA = glatiramer acetate; GM = gray matter; IFNβ = interferon beta; IM = intramuscular; IVIg = intravenous immunoglobulin; IVMP = IV methylprednisolone; MS = multiple sclerosis; NA = normal appearing; NS = not significant; OLC = open label controlled; PG = parallel group; PLC = placebo-controlled; PP = primary progressive; RR = relapsing-remitting; S = significant; SC = subcutaneous; SP = secondary progressive; WM = white matter.

Disclosure: The authors report no disclosures.

Received September 4, 2007. Accepted in final form February 5, 2008.

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