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Treatment of Acute Exacerbations

In the past management of MS exacerbations consisted principally of continuous enforced rest [2]. At the onset of an exacerbation, rest relieves (or prevents) fatigue. Thankfully, the injudicious use of extended periods of rest has given way to the enthusiastic use of physical rehabilitation.

The senior author’s career has spanned the era of validation and FDA approval of corticotrophin (adrenocorticotropic hormone/ACTH) [122] and the subsequent introduction and use of high-dose intravenous steroids for the management of exacerbations of multiple sclerosis. Dr. Leo Alexander, Harvard Medical School, initially used corticotrophin because steroids (that he hypothesized should be helpful) were not available (personal communication). The effectiveness of corticotrophin was established by multiple controlled trials, the first for any MS treatment [178]. The pivotal trial was a multicenter double-blind placebo-controlled trial was published in Neurology 1970 and became the basis of the FDA approval in 1978. No other drug has been validated as an effective treatment for exacerbations of MS. However, 40 years ago neurologists at the Montreal Neurological Institute, including the senior author with other MS physicians, first employed high-dose intravenous steroids in patients diagnosed with MS. The use of high-dose parenteral steroids was limited to patients who had lost vision, in one or both eyes due to optic neuritis, or who were acutely paraplegic due to acute myelitis. In retrospect, these patients probably had neuromyelitis optica rather than MS. On the basis of the analogy with trauma and tumor management, it was hypothesized that that acute severe edematous swelling of the optic nerve or spinal cord resulted in complicating ischemia due to the limited capacity to expand within the dura spaces. Although patients often improved rapidly, frequent complications of high-dose therapy problems were encountered. Gastrointestinal complications are now rare, but psychiatric disturbances, infectious complications, osteoporosis, and aseptic necrosis of the hip and other bones which are side effects are not rare. Despite weak evidence of benefit from the single-blind (intravenous) optic neuritis treatment trial indicating shortterm benefit [178, 179], no well-organized appropriate sized, double-blind trials have been carried out to date. The double-blind oral steroid use portion of the optic neuritis trial showed clearly that oral steroids were deleterious to patients with optic neuritis (most of whom would develop clinically definite multiple sclerosis). Patients receiving oral steroids subsequently experienced a doubled relapse rate of optic neuritis, apart from other manifestations of MS compared with oral placebo recipients. A German trial has confirmed experimental observations of increased damage from the use of steroids equivalent to doses used in human [180]. In patient with optic neuritis treated with steroids, treatment is associated with damage to the affected optic nerve that can be reduced by the concomitant administration of erythropoietin [181]. We interpret these results as evidence that oral steroids, alone, should not be used in the management of MS. It is important to note that a neuroprotective effect for neurons from corticotrophin is well established [182-184]. Methylprednisolone, however, has recently been shown to induce programmed cell death (apoptosis) of neurons [180]. Because of the effectiveness, and the neuroprotective effect, of corticotrophin, we continue to favor its use.

A trial of natalizumab for the management of acute exacerbations failed to influence the outcome of such clinical exacerbations [185]. The drug, however, did reduce the risk of new MRI brain lesions over the subsequent 12 weeks following a single infusion. Despite its failure to induce a more rapid recovery from exacerbations, natalizumab did improve the sense of well-being of the drug recipients, also. Benefit was observed in subsequent studies aimed at reducing the risk of MS exacerbations and/or sustained increase in disability also.

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