Steroids

Systematic reviews
Review detailsInterventionPopulationResultsQuality assessment+
Author (year)
Brusaferri (2000)[117]

Objective
To assess the effects of steroids on short and long term functional improvement and on the prevention of relapses (only results for patients receiving long-term therapy reported here).

Number of included studies
4 placebo controlled RCTs (n = 637)
Adrenocorticotrophic hormone (ACTH) (n=1)

Prednisolone (n=1)

Methylprednisolone (n=2)

Treatment duration: 9–18 months
Patients with mixed MS and primary progressive MS (PPMS).No significant effect on long-term functional improvement or on relapse recurrence.

A number of the studies reported both major and minor side effects associated with steroid treatment. Major side-effects included herpes simplex, herpes zoster, severe ankle oedema, femur fracture, acute anxiety and severe depression. The reported minor side effects were hypertension, cardiac arrhythmia, weight gain, sleep disturbance, metallic taste, full face and facial acne.
1: Good
2: Good
3: Good
4: Good
5: Fair
RCTS and CCTs
Study DetailsInterventionPopulationResultsQuality assessment*
Author (year)
Beretta (1997)[146]

Study design
CCT
Intervention 1
3 administrations of methylprednisolone, 2 g in 12 hours over 7 days (during exacerbations) and 1 methylprednisolone administration every 2 months. (Intra-venous)

Control
Only treated during exacerbation (schedule as per intervention group)

Treatment duration
months – 3 years

Duration of follow-up
6 months – 3 years
Condition
MS only

Number of patients Total: 27 (16 int, 11 control)
RR: 27

Age: 33.1

Duration of MS: 5.6

Inclusion criteria: Patients with a diagnosis of relapsing-remitting MS (Poser); EDSS score 0.5–5, and a follow-up period of longer than 6 months.
Relapse free patients:
Intervention 1 vs control: + ve

Incidence of relapses
Intervention 1 vs control: + ve

Drop outs:
Patients had to be followed up for 6 months to be included; 2 were only followed for 2 months and so were excluded (no details of treatment).
Adverse effects:
In the intervention group1 patient had acute worsening of a pre-existing depressive syndrome and 4 had a mild increase in serum glucose after steroid administration.
1: No
2: No
3: No
4: Not clear
5: No
6: Yes
Author (year)
Boman (1966)[143]

Study design
RCT
Intervention 1
ACTH (4ml twice a day for 10 days; 6ml once a day for 5 days; 4ml once a day for 5 days then 2ml once a day for 5 days, Intra-venous)

Control
Placebo (same as active)

Treatment duration
25 days

Duration of follow-up
Not reported
Condition
MS only

Number of patients Total: 25 (13 in ACTH; 12 in placebo)

Age: Range: 19–60 years

Duration of MS: 6 years

Inclusion criteria: Diagnosis of MS according to the Alexander criteria
Dysarthia: no difference
Muscular strength: no difference
Muscular tone: no difference
Coordination: no difference
Muscle reflexes: no difference
Change in symptoms: no difference

Drop outs:
Not reported
Adverse effects:
Not reported
1: No
2: No
3: Yes
4: Yes
5: Not clear
6: Not clear
Author (year)
Cazzato (1995)[144]

Study design
randomised cross-over
Intervention 1
1 g methylprednisolone for 5 days followed by oral prednisone (50 mg) daily for 2 days and 25 mg daily for last 2 days

Control
Placebo solution and tablets

Treatment duration
9 days

Duration of follow-up
8 months
Condition
MS only

Number of patients Total: 35

PP: 35

Age: 44.2 years

Duration of MS: 7.7 years

Inclusion criteria: Patients with primary progressive MS (Poser).
Pyramidal function: + ve
Cerebellar symptoms: + ve
Brainstem impairment: no difference
Sensitivity disorders: + ve
Urinary disorders: no difference
Overall EDSS score: + ve
Visual disorders: no difference
Mental disorders: no difference

Drop outs:
None.
Adverse effects:
Minor side effects of metallic taste, insomnia, weakness, headache and mood changes.
1: Yes
2: Not clear
3: Yes
4: Yes
5: Yes
6: Yes
Author (year)
Fierrro (2002)[121]

Study design
RCT
Intervention 1
Methylprednisolone (1 g/day for 5 days), Intra-venous

Control
Methylprednisolone (2 g/day for 5 days), Intra-venous.

Treatment duration
5 days

Duration of follow-up
21 days
Condition
MS only

Number of patients Total: 24 (12 high dose, 9 low dose)
RR: 24

Age: 32 years (range 18 – 49).

Duration of MS: 4.1 years

Inclusion criteria: Patients with clinically definite relapsing remitting MS (Poser) seen within 1 week from the onset of relapse were included. Patients with a concomitant fever, a history of epilepsy, head neurosurgery or the possession of a cardiac pacemaker were excluded. Patients with diabetes, severe hypertension or peptic ulcers were also excluded.
Motor Threshold (MEP) (MT, CMCT and SP measures): no difference
Central motor conduction time (MEP): no difference
Silent Period (MEP): no difference
Motor strength of upper limbs (Medical research council scale): no difference
EDSS: no difference
Drop outs:
3 in total, 1 in the high dose and 2 in the low dose group. All were intolerant of transcranical magnetic stimulation.
Adverse effects:
No adverse effects of IVMP were reported. However, 3 patients who dropped out were intolerant to the transcranical magnetic stimulation.
1: Yes
2: Not clear
3: Yes
4: Yes
5: No
6: Yes
Author (year)
Goodkin (1987)[158]

Study design
RCT
Intervention 1
Methylprednisolone (500 mg (high dose) administered once each day for 3 days followed by tapering course of oral methylprednisolone on days 4 – 14, with dosage starting at 64 mg and reduced to 8 mg., every 2 months)Intra-venous

Control
Methylprednisolone (10 mg (low dose) administered once each day for 3 days followed by tapering course of oral methylprednisolone on days 4 – 14, with the dosage starting at 10 mg and reduced to 2 mg. every 2 months)

Treatment duration
2 years

Duration of follow-up
2 years
Condition
MS only

Number of patients Total: 108 (54 in each group)
SP: 108

Age: not stated

Duration of MS: not stated

Inclusion criteria: Patient's with a definite diagnosis of secondary progressive MS; 1 or more exacerbations during the 2 years preceding study entry; progression of 0.5 or more EDSS points sustained for 5 or more months; EDSS score of 4 – 6.5; AI score of 6.0; age 21 – 60 years; disease duration longer than 1 year from onset of first symptom of MS. Patient's with progressive disease from onset; immunosuppressant drug use during the 1 year preceding study entry, corticosteroid use during 4 weeks prior to study entry, and prior exposure to total lymphoid irradiation were excluded.
Sustained treatment failure (worsening of EDSS score by 1 point for baseline score of 4–5 or 0.5 points for baseline score of 5.5 – 6.5; worsening on AI by 1 point; worsening of 20% on BBT or 9-HPT; 2 exacerbations within 11 successive months): no difference

Drop outs:
18 in total. 3 high-dose patients stopped treatment due to: depression, anxiety and insomnia (1), insomnia and dyspepsia (1), acne (1). Fifteen (9 low-dose and 6 high-dose) patients were lost to follow-up. No reason is stated for the loss.
Adverse effects:
There were 10 instances of serious toxicity, but only 3 related to therapy - a psychotic reaction, back pain with uncomplicated vertebral compression fracture and aseptic meningitis (all occurred within the high-dose group). Overall significantly more high-dose than low-dose patients experienced adverse events, however intervention/drug cessation was only required in 1 case.
1: Yes
2: Not clear
3: Yes
4: Yes
5: Yes
6: Yes
Author (year)
Mertin (1982)[145]

Study design
RCT
Intervention 1
Prednisolone, azathioprine and anti-lymphocyte globulin (ALG) (Prednisolone (initially 150 mg daily, tapered down to 20 mg & discontinued after 4 weeks), azathioprine (3 mg/kg per day for 15 months) ALG 500 – 750 mg daily for 15 intravenous infusions).

Control
Placebo (Dummy preparations)

Treatment duration
15 months

Duration of follow-up
150 weeks
Condition
MS only

Number of patients Total: 45 (int 21, control 24)
RR: 45

Age: not stated

Duration of MS: not stated

Inclusion criteria: Patient's with a definite diagnosis of MS (McAlpine); aged between 15 – 45 and an average of at least 1 relapse per year in the 2–3 years prior to study entry.
Annual relapse rate: no difference

VEP latency: + ve

EDSS score: no difference

Drop outs:
2, 1 in each group withdrew after the initial treatment phase (no reason stated).
Adverse effects:
Side effects due to the administration of ALG were: mild fever, arthralgia, tachycardia, chills and both localised and generalised skin rash (in 7 patients the severity of allergic reaction necessitated the termination of ALG treatment after 6 – 10 infusions). Azathioprine administration alone: mild anaemia, recurrent pneumonia and gastric irritation were observed (treatment in 2 patients had to be discontinued at 6 and 11 months).
1: Yes
2: Not clear
3: Yes
4: Yes
5: No
6: No
Author (year)
Rinne (1967)[142]

Study design
RCT
Intervention 1
zinc hydroxide corticotrophin (90 IU) daily
Intervention 2
zinc hydroxide corticotrophin (30 IU) daily

Control
placebo

Treatment duration
35 days

Duration of follow-up
not stated
Condition
MS only (28 were stable, 22 were in relapse.

Number of patients Total: 50 (22 int 1,8 int 2, 20 control)

Age: not stated

Duration of MS: not stated

Inclusion criteria: Patients with either chronic progressive or relapsing-remitting MS.
Improvement in Alexander score (patients with acute exacerbations): no difference High and low dose results reported together.
Improvement in Alexander score (patients with chronic progressive MS)
Intervention 1 vs control: no difference

Drop outs:
None reported.
Adverse effects:
Mild leucocytosis, 1 case of steroid diabetes, an increase in blood pressure, oedema, acne on the face or chest and slight hirsutism in female patients was observed in both the treatment groups.
1: No
2: Not clear
3: Not clear
4: Not clear
5: Not clear
6: Not clear
Author (year)
Zivadinov (2001)[147]

Study design
RCT
Intervention 1
Pulsed IVMP (1 g/day for 5 days with an oral prednisone taper of 50 mg for 2 days followed by 25 mg for 2 days) and pulsed IVMP for relapses as required. (Every 4 months for 3 years and then every 6 months for a further 2 years) Intra-venous

Control
IVMP (1 g/day for 5 days) given only for relapses.

Treatment duration
years

Duration of follow-up
5 years
Condition
MS only

Number of patients Total: 88 (43 int, 45 control)
RR: 88

Age: 32

Duration of MS: 5.7

Inclusion criteria: Clinically definite MS (Poser) with a relapsing remitting course; aged 18 – 60 years; disease duration of 1 – 10 years, EDSS score of < 5.5. Patients who had received immunomodulatory or immunosuppressive treatment in the 2 years preceding study entry or who were currently in exacerbation or experiencing progression were excluded.
T2 lesion volume: no difference

T1 lesion volume: + ve

Brain parenchymal volume: + ve

Annual relapse rate: no difference

EDSS: + ve

Drop outs:
4 patients in the intervention group dropped out, 2 due to adverse events and laboratory abnormalities, 1 due to deviation from the protocol and 1 due to personal decision. 3 patients in the control group dropped out, 1 due to wishing to discontinue treatment and 2 due to deviation from the protocol.
Adverse effects:
There were 2 serious adverse events in the pulsed IVMP group - acute glomerulonephritis and severe osteoporosis. Almost all the patients reported “metallic taste” sensation during the treatment.

In both groups minor short-term adverse events (insomnia, pyrosis, anxiety-nervousness, constipation, acneform rash, and polyphagia) were frequent. Long-term adverse events were uncommon but included osteoporosis, arterial hypertension and recurrent herpetic infections.
1: Yes
2: Not clear
3: No
4: Yes
5: No
6: Yes

RCT/CCT quality assessment

1=Was the study truly randomised?

2=Was treatment allocation concealed?

3=Were patients blinded?

4=Were outcome assessors blinded?

5=Was an intention to treat analysis performed?

6=Were groups comparable at baseline?

Studies were scored as yes/no/not reported for each of these items.

Systematic review quality assessment

1 = inclusion criteria

2=literature search

3=quality assessment

4=study details

5= pooling

Studies were scored as good/fair/poor/not reported for each of these items.

From: Appendix I, Evidence tables

Cover of Multiple Sclerosis
Multiple Sclerosis: National Clinical Guideline for Diagnosis and Management in Primary and Secondary Care.
NICE Clinical Guidelines, No. 8.
National Collaborating Centre for Chronic Conditions (UK).
Copyright © 2004, Royal College of Physicians of London.

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