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Steroids

The role of steroids for MS relapses has been accepted for many years. Most neurologists now prescribe steroids for acute relapses for people with relapsing-remitting MS. The evidence seems clear that they shorten recovery time from individual relapses. This contrasts with any of the other agents currently available, none of which appears to have much effect on improving the recovery from an acute relapse. For instance, natalizumab which potently affects the relapse rate in MS has no effect on recovery from an acute relapse.1 What is not so clear about steroids is whether the actual amount of recovery is improved, nor the optimal dose, appropriate route of administration, or whether there is any benefit long term.

‘Steroids’ is the accepted shortening of the term corticosteroids. Steroids in general are found naturally in plants and animals, but corticosteroids are those particular steroids secreted into the bloodstream by the adrenal gland. Many are now also synthesised in the laboratory.

Studies of people with MS relapses who are being treated with steroids show that the steroids work by decreasing the levels of the ‘bad’ immune chemicals and by making the cell membranes of the white cells more pliable and less sticky.2 It is interesting to note how similar this is to the mechanism in which diet and essential fatty acids supplements work, but without side-effects. Other evidence suggests that there is also an effect on the way the brain interprets the messages coming to it from the body’s nerves.3 MRI studies also show that steroids significantly decrease the amount of swelling around individual MS lesions, causing better nerve transmission through these affected areas. These effects are seen on MRI within hours of taking the first dose.

Side-effects of Steroids

Steroids for MS are safe when used in short courses of 5-7 days or less. A few rare cases of bone problems have been reported, but these are exceedingly unlikely. When used continually long term they can cause serious problems including weight gain, fluid retention, increased risk of infection, risk of stomach ulcers, muscle weakness, changes in behaviour including depression or psychosis, cataracts and osteoporosis. Long-term use is not a good idea in any condition, unless there is no real alternative.
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Randomised Controlled Trials of Steroids in MS

Studies over many years have shown a beneficial effect in recovery from acute relapses in MS when the relapses are treated with intravenous steroids. Milligan and colleagues randomised fifty patients to receive either methylprednisolone (MP) 500mg intravenously (IV) for five days or inactive placebo.4 Assessments were carried out at 1 and 4 weeks after the treatment by a ‘blinded’ neurologist; 73 per cent of MP-treated patients improved compared with 29 per cent of those on placebo. The p value was 0.001. The treated group contained patients with classic relapsing-remitting MS, but also patients with chronic progressive MS, and both categories benefited from MP. This study caused most neurologists around the world to subsequently offer patients IV MP for relapses.

Although most inflammatory diseases for which steroids have been used have shown similar benefit for IV and oral routes of administration, most neurologists have used steroids for MS only by the IV route. This seems to have stemmed from the results of a study by Beck and co-workers in the early 1990s.5 They studied the use of steroids in optic neuritis. This is where the nerves to the eyes become inflamed, causing visual disturbance. The majority of people who develop this condition eventually go on to get MS. Beck and colleagues showed that IV MP seemed to delay the development of MS in these patients for longer than oral MP. While this may have just been a quirk in the way the results fell in that particular study, it was very influential in its effect on the prescribing habits of neurologists. Most tended to give only IV steroids after the results of that study were published, even for people who had typical MS relapses and not optic neuritis.

This was first challenged by the results of a small study of thirty-five patients, which showed equivalent benefit for oral and IV steroids.6 A more recent well-constructed RCT compared oral vs IV steroids in 80 patients.7 There was no difference between the groups in terms of degree of neurological improvement at 1, 4, 12 or 24 weeks after therapy. Indeed, there was a slight trend to better results for the orally treated group.

The most recent of these studies was from Copenhagen. Sellebjerg and co-workers randomised 51 patients with an acute relapse of MS lasting less than four weeks to receive either placebo orally or oral prednisolone 500mg per day for five days, then a tapering-off dose.8 After 1, 3, and 8 weeks, 4 per cent, 24 per cent, and 32 per cent in the placebo group and 31 per cent, 54 per cent, and 65 per cent in the prednisolone group improved one point on the Kurtzke Scale score (all p<0.05). Patients also rated their symptoms as having improved much more with the steroids at 3 (p = 0.005) and 8 weeks (p = 0.0007). No significant side-effects were noted.

This study confirmed the very significant improvements people can get by using steroids when they have a relapse. Most doctors will now offer this therapy for a relapse. But if only IV steroids are offered, it is worth mentioning the evidence that oral steroids are just as good. From the patient’s point of view, oral is really much better. For a start no special expertise is needed to administer the drug, which means no day hospitals and inconvenience. Secondly, there is no discomfort, bruising, and so on.

There is still however considerable debate about the optimal dosage of steroids for multiple sclerosis and the duration of the course. Most neurologists use them for selected relapses but not all, and about 50% use them for all relapses. Similarly there is a lot of variation in whether oral or IV steroids are usually used. UK neurologists overwhelmingly favour IV, despite the evidence presented above that oral is likely to be just as effective. Over 90% use IV steroids, and only about 5% routinely use oral steroids.9

The UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend either 500mg-1g of IV methylprednisolone for 3-5 days, or 500mg-2g oral prednisone for 3-5 days. The oral and intravenous doses have been shown to be roughly equivalent in terms of biological availability.10 The NICE guidelines suggest that steroids shouldn’t be used more than three times a year, or for more than three weeks at a time in any given episode.

A possibility raised recently is that the course of steroids may be more effective if it is given at night.11 Because there is a natural rhythm of steroid secretion in the body, varying between day and night, Israeli researchers compared outcomes and side effects of steroid therapy for relapses between one groups of people with MS given the treatment during the day and the other at night.11 The outcome was better for those receiving the treatment at night, side effects were fewer, and patients expressed a clear preference for night time treatment.

Most neurologists treat only some MS relapses with steroids. They argue that only attacks which are severe and likely to leave some disability should be treated. From the point of view of a patient, all relapses can leave lasting symptoms which can be quite distressing, even if just disturbances in sensation, and some of these sensory lesions may result in quite a bit of pain in the long run. Therefore many authorities favour treating most relapses, unless they are very frequent, in which case a maintenance immunosuppressant medication might be best considered. The NICE guidelines recommend treating ‘an acute episode sufficient to cause distressing symptoms or an increased limitation on activities’.12 So what constitutes ‘distressing’ is clearly up to the patient.

It may be a good idea to discuss with the neurologist the possibility of keeping a dose of steroids at home in case of a relapse, and what sort of symptoms might warrant starting the course. Sometimes it can take quite a while to get in to see a neurologist, and the earlier these drugs are started in a relapse, the more effective they are likely to be. Many patients and their neurologists will be comfortable with this sort of approach, although clearly it is not for everyone. Not everyone feels confident enough about what exactly constitutes a relapse.
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Overview

There is convincing evidence that steroids are useful in improving the recovery after a relapse of MS. It is probable that steroids delay the onset of the next episode as well. The oral route seems to be as effective as the IV route. There is also likely to be a role for long-term intermittent high dose steroids, but more work is needed before this will be clear. For most relapses, there should be no delay in starting a short course of steroids.
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  1. O’Connor PW, Goodman A, Willmer-Hulme AJ, et al. Randomized multicenter trial of natalizumab in acute MS relapses: and MRI effects. Neurology 2004; 62:2038-2043
  2. Wandinger KP, Wessel K, Trillenberg P, et al. Effect of high-dose methylprednisolone administration on immune functions in multiple sclerosis patients. Acta Neurol Scand 1998; 97:359-365.
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  9. Tremlett HL, Luscombe DK, Wiles CM. Use of corticosteroids in multiple sclerosis by consultant neurologists in the United Kingdom. J Neurol Neurosurg Psychiatry 1998; 65:362-365
  10. Morrow SA, Stoian CA, Dmitrovic J, et al. The bioavailability of IV methylprednisolone and oral prednisone in multiple sclerosis. Neurology 2004; 63:1079-1080
  11. Glass-Marmor L, Paperna T, Ben-Yosef Y, et al. Chronotherapy using Corticosteroids for Multiple Sclerosis Relapses. J Neurol Neurosurg Psychiatry 2006
  12. National Institute for Clinical Excellence. Multiple sclerosis. Management of multiple sclerosis in primary and secondary care. London: National Institute for Clinical Excellence, 2003