Why steroids are prescribed for treating MS
The use of steroids in the management of acute MS relapses has been commonplace for many years. The evidence appears clear that they shorten the time taken to recover from a relapse in people with relapsing-remitting MS., with new symptoms resolving quicker in those taking a short course of steroids (usually three to five days), than those taking a placebo or no treatment. This is not the case with the other DMDs, none of which appears to have any effect on improving recovery time from an individual relapse.
It is now also clear that steroids are most effective when started soon after the onset of a relapse (up to fourteen days), but have no effect on the level of recovery from a relapse, or on the long-term course of someone’s MS. For this reason, and also due to potential side effects, steroids are not always prescribed for every relapse episode, but often reserved for more severe or debilitating symptoms, such as new walking difficulties or affecting eyesight.
In the interests of clarity, it should be stated that not all steroids are created equal. When we hear the term “steroid” we often think of huge bodybuilders, and athletes using drugs to enhance their performance. These are the anabolic steroids. Whilst they do share some properties, they should be considered as very different from those used in MS and other inflammatory conditions; the corticosteroids.
‘Steroids’ is the commonly shortened version of the term corticosteroids. Whilst steroids are produced by many plants and animals, corticosteroids technically refer to those specifically released from the adrenal glands, sitting on top of the kidneys. The synthetic forms now widely available are many times more potent than the natural forms, and are used in various preparations to treat a range of conditions, such as eczema and psoriasis, asthma, rheumatoid arthritis and systemic lupus erythematosus (SLE).
Steroids have many effects on the human body, but their benefits in MS are as a result of their anti-inflammatory properties. They suppress the immune system by altering the balance of pro and anti-inflammatory messengers that instruct the white blood cells to attack (in this case, mistakenly against the myelin coating of certain nerve cells). Steroids also make the cell membranes of white blood cells more flexible and less sticky, meaning that they are less able to attach to other cells and damage or destroy them. This is actually a very similar mechanism to the longer-term effects seen with a low saturated fat diet and omega-3 fatty acid supplementation.
MRI scans of the brain show that swelling around individual MS lesions reduces rapidly (often within hours) of a first dose of steroids, allowing improved nerve signal transmission in the affected areas, and a reduction in symptoms.
Whilst they are generally safe when used in short courses of up to seven days, they do come with a significant side effect profile, especially if used continually in the long-term. They can cause weight gain, fluid retention, an increased risk of infection, stomach ulcers (they should be prescribed with a tablet to protect the stomach lining e.g. omeprazole), depression or psychosis, muscle weakness, cataracts and osteoporosis. It is for this reason that it is generally recommended that their use is limited to three courses per year, and for no more than three weeks at a time.
In the past, steroids were often prescribed in the intravenous (IV) form when treating MS relapses. This very often meant hospital admission, with all the distress and disruption that is associated, not to mention the discomfort of IV injections and risk of hospital-acquired infections. The evidence is now clear, however, that a course of oral steroids is just as effective as IV, and significantly more convenient for the patient. There is no need to taper the dose after the initial course, and the shorter the course, the safer the treatment.
Not all neurologists will prescribe a course of steroids for all relapses, but rather reserve their use for more severe episodes that are most likely to cause more disability. This is not unreasonable, but it is perhaps worth discussing the possibility of having a prescription at home, so that you can begin a course quickly in the case of a relapse. Whilst starting a course of steroids early in a relapse gives the best results, it is worth waiting at least 48 hours from the onset of symptoms, as they may not represent a true relapse or require any treatment.
Rarely, steroids can be given at regular intervals in an attempt to reduce the frequency of relapses. Known as intermittent pulsed dosing, the drug can be given every month or alternate month at a similar dose to that used to treat relapses. At present there are only the results of a few small studies, but it appears that this form of treatment reduces the number of new lesions on MRI, relapse rates and disability progression rates. In progressive MS, early evidence shows a benefit in terms of walking speed and distance, when a long-acting steroid is injected directly into the spinal fluid, much like a lumbar puncture. Larger scale studies are now required to ascertain the long-term safety and efficacy before this would become a mainstream treatment option, perhaps in addition to the use of another DMD.
Natalizumab potently affects the relapse rate in MS, but it has no effect on recovery from an acute relapse. What is not clear about steroids is:
- Whether the actual amount of recovery is improved
- What the optimal dose is
- The appropriate route of administration
- Whether they offer any long-term benefit
‘Steroids’ is the accepted shortening of the term corticosteroids.
Steroids in general are found naturally in plants and animals, but corticosteroids are those steroids secreted into the bloodstream by the adrenal gland. Many are now also synthesized in the laboratory.
Studies of people being treated with steroids for MS relapses show that steroids work by decreasing the levels of the ‘bad’ immune chemicals while making the white cells’ membranes more pliable and less sticky (note how similar this is to the mechanism by which diet and essential fatty acids supplements work – but those have no side effects).
Other evidence suggests steroids affect how the brain interprets messages coming from the body’s nerves.
MRI studies 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 when used for treating MS
Steroids are safe for MS when used in short courses of five to seven days or less. A few rare cases of bone problems have been reported, but these are exceedingly unlikely.
When used continually on a long-term basis, they can cause serious problems including weight gain, fluid retention, muscle weakness, cataracts, osteoporosis, increased risk of infection or stomach ulcers, and changes in behavior, including depression or psychosis.
Long-term use is not a good idea in any condition, unless there is no real alternative.
RCTs of steroids in MS
Studies over many years have shown that intravenous steroids provide a beneficial effect in recovery from acute relapses in MS. Milligan and colleagues randomized 50 patients to receive either methylprednisolone (MP) 500 mg intravenously (IV) for five days or inactive placebo.
Assessments were carried out by a ‘blinded’ neurologist at one and four weeks after the treatment; 73% of MP-treated patients had improved, compared to just 29% of those on placebo.
The treated group included patients with classic relapsing-remitting MS, and also patients with chronic progressive MS; both 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.
They studied the use of steroids in optic neuritis, wherein the nerves to the eyes become inflamed, causing visual disturbance. Most people who develop this condition eventually get MS. Beck and colleagues showed that IV MP seemed to delay the development of MS in these patients longer than oral MP did.
While this may have been a quirk of that particular study, it turned out to be very influential: After the study was published, most neurologists tended to give only IV steroids – even to people who had typical MS relapses and not optic neuritis.
This was first challenged by the results of a small study of 35 patients, which showed equivalent benefit for oral and IV steroids.
A more recent well-constructed RCT compared oral steroids to IV steroids in 80 patients.
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.
In Copenhagen, Sellebjerg and co-workers randomized 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, followed by a tapering-off dose.
After 1, 3, and 8 weeks, 4%, 24% and 32% in the placebo group improved one point on the Kurtzke Scale score, versus 31%, 54%, and 65% in the prednisolone group.
Patients receiving steroids also rated their symptoms as having improved much more at three and eight weeks. No significant side effects were noted.
Are needles needed to take MS steroids?
This study confirmed the very significant improvements steroids can provide during a relapse. Most doctors now offer this therapy for a relapse.
But if a doctor offers only IV steroids, it is worth mentioning the evidence that oral steroids are just as good. From the patient’s point of view, oral steroids are really much better, because:
- No special expertise is needed to administer the drug, which means
- No hospital visits and inconvenience result, and
- There is no discomfort, bruising, and so on
There is still considerable debate about the optimal dosage and duration of steroids for MS. Most neurologists use them for selected relapses, 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 favor IV, despite the above evidence that oral is likely to be just as effective.
More than 90% use IV steroids, and only about 5% routinely use oral steroids.
The UK National Institute for Health and Clinical Excellence (NICE) guidelines recommend either 500mg to 1g of IV methylprednisolone for three to five days, or 500mg to 2g of oral prednisone for three to five days.
The oral and IV doses have been shown to be roughly equivalent in terms of biological availability.
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.
It is possible that the course of steroids is more effective if given at night.
Because the body has a natural rhythm of steroid secretion, varying between day and night, Israeli researchers compared outcomes and side effects of steroid therapy for relapses, giving one group of people with MS the treatment during the day and administering the treatment at night to the other group.
The night-time group had better outcomes with fewer side effects, and patients expressed a clear preference for night-time treatment.
Most neurologists treat only some MS relapses with steroids. They argue that only severe attacks likely to leave some disability should be treated.
From a patient’s point of view, all relapses can leave lasting and distressing symptoms (even if they’re only disturbances in sensation), and some sensory lesions may result in long-term pain.
That is why many authorities favor treating most relapses, unless they are very frequent, in which case a maintenance immunosuppressant medication might be best.
The NICE guidelines recommend treating ‘an acute episode sufficient to cause distressing symptoms or an increased limitation on activities.’ Just what constitutes ‘distressing’ is up to the patient.
It may be a good idea to discuss with your doctor the possibility of keeping a dose of steroids at home in case of a relapse, and also clarifying which symptoms might warrant starting the course.
It can take 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 approach, although not everyone feels confident enough to decide what exactly constitutes a relapse.
- There is convincing evidence that steroids help improve recovery after a relapse
- They probably delay the onset of the next episode as well
- The oral route seems to be as effective as the IV route
- There is likely to be a role for long-term intermittent high-dose steroids, but more research is needed before this is clear
- For most relapses, there should be no delay in starting a short course of steroids
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. ActaNeurolScand 1998; 97:359-365
3. Filipovic SR, Drulovic J, Stojsavljevic N, et al. The effects of high-dose intravenous methylprednisolone on event-related potentials in patients with multiple sclerosis. J NeurolSci 1997; 152:147-153
4. Milligan NM, Newcombe R, Compston DA. A double-blind controlled trial of high dose methylprednisolone in patients with multiple sclerosis: 1. Clinical effects. J NeurolNeurosurg Psychiatry 1987; 50:511-516
5. Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. NEngl J Med 1993; 329:1764-1769
6. Alam SM, Kyriakides T, Lawden M, et al. Methylprednisolone in multiple sclerosis: a comparison of oral with intravenous therapy at equivalent high dose. J NeurolNeurosurg Psychiatry 1993; 56:1219-1220
7. Barnes D, Hughes RA, Morris RW, et al. Randomised trial of oral and intravenous methylprednisolone in acute relapses of multiple sclerosis. Lancet 1997; 349:902-906
8. Sellebjerg F, Frederiksen JL, Nielsen PM, et al. Double-blind, randomized, placebo-controlled study of oral, high-dose methylprednisolone in attacks of MS. Neurology 1998; 51:529-534
9. Tremlett HL, Luscombe DK, Wiles CM. Use of corticosteroids in multiple sclerosis by consultant neurologists in the United Kingdom. J NeurolNeurosurg 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 NeurolNeurosurg 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