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Corticosteroids for treating nerve damage in leprosy (Review)
Van Veen NHJ, Nicholls PG, Smith WCS, Richardus JH
Van Veen NHJ, Nicholls PG, Smith WCS, Richardus JH.

Corticosteroids for treating nerve damage in leprosy.
Cochrane Database of Systematic Reviews 2016, Issue 5. Art. No.: CD005491.
DOI: 10.1002/14651858.CD005491.pub3.
www.cochranelibrary.com

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 3
BACKGROUND.............................................................................................................................................................................................. 6
OBJECTIVES.................................................................................................................................................................................................. 6
METHODS..................................................................................................................................................................................................... 6
RESULTS........................................................................................................................................................................................................ 8
Figure 1.................................................................................................................................................................................................. 9
DISCUSSION.................................................................................................................................................................................................. 12
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 14
ACKNOWLEDGEMENTS................................................................................................................................................................................ 14
REFERENCES................................................................................................................................................................................................ 15
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 18
DATA AND ANALYSES.................................................................................................................................................................................... 24
Analysis 1.1. Comparison 1 Corticosteroids versus placebo, Outcome 1 Improvement in sensory score after one year................ 25
Analysis 1.2. Comparison 1 Corticosteroids versus placebo, Outcome 2 Proportion with sensory improvement after one year...... 25
Analysis 1.3. Comparison 1 Corticosteroids versus placebo, Outcome 3 Proportion with serious adverse events......................... 26
Analysis 1.4. Comparison 1 Corticosteroids versus placebo, Outcome 4 Improvement in motor score after one year................... 26
Analysis 1.5. Comparison 1 Corticosteroids versus placebo, Outcome 5 Proportion with motor improvement after one year....... 27
Analysis 2.1. Comparison 2 High-dose versus low-dose five-month course corticosteroids, Outcome 1 Proportion needing 27
additional corticosteroids during 12 months......................................................................................................................................
Analysis 3.1. Comparison 3 High-dose five-month versus three-month course corticosteroids, Outcome 1 Proportion needing 28
additional corticosteroids during 12 months......................................................................................................................................
Analysis 4.1. Comparison 4 Low-dose versus short-course corticosteroids, Outcome 1 Proportion needing additional 28
corticosteroids during 12 months........................................................................................................................................................
Analysis 5.1. Comparison 5 Intravenous methylprednisolone and oral prednisolone versus intravenous normal saline and oral 29
prednisolone, Outcome 1 Adverse events...........................................................................................................................................
ADDITIONAL TABLES.................................................................................................................................................................................... 29
APPENDICES................................................................................................................................................................................................. 35
FEEDBACK..................................................................................................................................................................................................... 38
WHAT'S NEW................................................................................................................................................................................................. 40
HISTORY........................................................................................................................................................................................................ 40
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 41
DECLARATIONS OF INTEREST..................................................................................................................................................................... 41
SOURCES OF SUPPORT............................................................................................................................................................................... 42
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 42
INDEX TERMS............................................................................................................................................................................................... 42
Corticosteroids for treating nerve damage in leprosy (Review) i

Informed decisions.

[Intervention Review]
Corticosteroids for treating nerve damage in leprosy
Natasja HJ Van Veen1, Peter G Nicholls2, W Cairns S Smith3, Jan Hendrik Richardus1
1Department of Public Health, Erasmus Medical Center, Rotterdam, Netherlands. 2School of Health Sciences, University of Southampton,
Southampton, UK. 3Public Health, University of Aberdeen, Aberdeen, UK
Contact address: Natasja HJ Van Veen, Department of Public Health, Erasmus Medical Center, PO Box 2040, Rotterdam, 3000 CA,
Netherlands. nhjvanveen@gmail.com, nhjvanveen@gmail.com.
Editorial group: Cochrane Neuromuscular Group.

Publication status and date: Edited (no change to conclusions), published in Issue 3, 2017.
Citation: Van Veen NHJ, Nicholls PG, Smith WCS, Richardus JH. Corticosteroids for treating nerve damage in leprosy. Cochrane Database
of Systematic Reviews 2016, Issue 5. Art. No.: CD005491. DOI: 10.1002/14651858.CD005491.pub3.
ABSTRACT
Background
Leprosy causes nerve damage that can result in nerve function impairment and disability. Corticosteroids are commonly used for treating
nerve damage, although their long-term effect is uncertain. This is an update of a review first published in 2007, and previously updated
in 2009 and 2011.
Objectives
To assess the effects of corticosteroids on nerve damage in leprosy.
Search methods
On 16 June 2015, we searched the Cochrane Neuromuscular Specialised Register, the Cochrane Central Register of Controlled Trials
(CENTRAL), MEDLINE, EMBASE, CINAHL Plus, and LILACS. We also checked clinical trials registers and contacted trial authors.
Selection criteria
Randomised controlled trials (RCTs) and quasi-RCTs of corticosteroids for nerve damage in leprosy. The comparators were no treatment,
placebo treatment, or a different corticosteroid regimen.
Data collection and analysis

The primary outcome was improvement in nerve function after one year. Secondary outcomes were change in nerve pain, limitations in
activities of daily living, limitations in participation, and adverse events. Two review authors independently extracted data and assessed
trial quality. When data were lacking, we contacted trial authors for additional information.
Main results
We included five RCTs involving 576 people. The trials were largely at low risk of bias, but we considered the quality of the evidence from
these trials as moderate to low, largely due to imprecision from small sample sizes. Two out of the five trials reported on improvement
in nerve function at one year. These two trials compared prednisolone with placebo. One trial, with 84 participants, treated mild sensory
impairment of less than six months' duration, and the other, with 95 participants, treated nerve function impairment of 6 to 24 months'
duration. There was no significant difference in nerve function improvement after 12 months between people treated with prednisolone
and those treated with placebo. Adverse events were not reported significantly more often with corticosteroids than with placebo. The
other three trials did not report on the primary outcome measure. One (334 participants) compared three corticosteroid regimens for
severe type 1 reactions. No serious side effects of steroids were reported in any participant during the follow-up period. Another trial
(21 participants) compared low-dose prednisone with high-dose prednisone for ulnar neuropathy. Two participants on the higher dose
of prednisone reported adverse effects. The last (42 participants) compared intravenous methylprednisolone and oral prednisolone with
Corticosteroids for treating nerve damage in leprosy (Review) 1
Informed decisions.

intravenous normal saline and oral prednisolone. The trial found no significant differences between the groups in the occurrence of adverse
events.
Authors' conclusions
Corticosteroids are used for treating acute nerve damage in leprosy, but moderate-quality evidence from two RCTs treating either
longstanding or mild nerve function impairment did not show corticosteroids to have a superior effect to placebo on nerve function
improvement. A third trial showed significant benefit from a five-month steroid regimen over a three-month regimen in terms of response
to treatment (need for additional corticosteroids). Further RCTs are needed to establish optimal corticosteroid regimens and to examine
the efficacy and safety of adjuvant or new therapies for treating nerve damage in leprosy. Future trials should address non-clinical aspects,
such as costs and impact on quality of life, which are highly relevant indicators for both policymakers and participants.
PLAIN LANGUAGE SUMMARY
Corticosteroids for treating nerve damage in leprosy
Review question
Are corticosteroids an effective treatment for nerve damage in leprosy?
Background
Leprosy is a long-term infectious disease. Leprosy bacteria cause damage to the skin and peripheral nerves (nerves outside the brain and
spinal cord). This damage can stop nerves from working normally and cause disability. Corticosteroids, especially prednisolone, are often
used to treat nerve damage in leprosy, but their long-term effect is uncertain.
Study characteristics
We conducted a wide search for reports of clinical trials of treatments for nerve damage in leprosy. We found five clinical trials that met
our criteria, involving 576 people with leprosy. Two of the included trials compared prednisolone with placebo. One of these trials, with 84
participants, recruited people who had mild abnormality of feeling of less than six months' duration and the other, with 95 participants,
assessed treatment effects in people with abnormal nerve function of 6 to 24 months' duration. A third trial, with 334 participants,
compared three 12-month corticosteroid regimens for severe type 1 reactions. Type 1 reactions are episodes in which nerves become
inflamed. The fourth trial (21 participants) compared a low dose of prednisone with a high dose of prednisone for people with damage
to the ulnar nerve (a nerve in the arm). The fifth trial (42 participants) compared intravenous methylprednisolone and oral prednisolone
with intravenous normal saline and oral prednisolone in people with a type 1 leprosy reaction or abnormal nerve function of no more than
six months' duration.
Key results and quality of the evidence
There was no important difference in improvement in nerve function between people treated with prednisolone or with placebo after
one year, according to two trials. More people on a three-month course of prednisolone failed to respond to treatment and required
extra corticosteroids compared to people on either a high-dose or a low-dose regimen of five months' duration. The trials comparing
corticosteroids with placebo and a trial comparing intravenous methylprednisolone and oral prednisolone with intravenous normal saline
and oral prednisolone found no differences in the occurrence of adverse events between groups. We considered the quality of the evidence
to be moderate to low. Although trials were well conducted and designed, they were largely small and did not always use proven measures
to capture the effects of corticosteroids.
The evidence in this review is up to date to June 2015.

SUMMARY OF FINDINGS

Summary of findings for the main comparison. Corticosteroids compared with placebo for treating nerve damage (< 6 months' duration) in leprosy
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Corticosteroids compared with placebo for treating nerve damage (< 6 months' duration) in leprosy
Patient or population: people with nerve damage (< 6 months' duration) in leprosy
Settings: Nepal and Bangladesh
Better health.
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Trusted evidence.
Intervention: corticosteroids (prednisolone started at 40 mg/day then gradually tapered)
Comparison: placebo
Outcomes Anticipated absolute effects* (95% Relative effect Number of par- Quality of the Comments
CI) (95% CI) ticipants evidence
(studies) (GRADE)
Risk with Risk with corti-
placebo costeroids
Improvement in sensory nerve function at 1 year Study population RR 1.01 (0.81 to 75 nerves ⊕⊕⊕⊝ -
1.27) (1 RCT) moderate 1
Defined as a reduction in sensory score by 3 or more 794 per 1000 802 per 1000
points from baseline
(643 to 1000)
Improvement in motor nerve function at 1 year - - - - - -
- not reported
Change in nerve pain and in nerve tenderness at 1 - - - - - -

year - not reported

Limitations in activities of daily living at 1 year - not - - - - - -
reported
Limitations in participation at 1 year - not reported - - - - - -
Adverse events Study population RR 0.83 (0.05 to 75 nerves ⊕⊕⊕⊝ -

12.77) moderate 1
Assessed as: occurrence of one or more major adverse 29 per 1000 24 per 1000 (1 RCT)
events requiring withdrawal of treatment (1 to 376)
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
3

CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence
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High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1Small sample size.
Better health.
Informed decisions.
Trusted evidence.

Summary of findings 2. Corticosteroids compared to placebo for treating nerve damage (6 to 24 months' duration) in leprosy
Corticosteroids compared to placebo for treating nerve damage (6 to 24 months' duration) in leprosy
Patient or population: people with nerve damage (6 to 24 months' duration) in leprosy

Setting: Nepal and Bangladesh
Intervention: corticosteroids (prednisolone starting at 40 mg/day and gradually tapered)
Comparison: placebo
Outcomes Anticipated absolute effects* (95% CI) Relative effect Number of par- Quality of the Comments
(95% CI) ticipants evidence
Risk with Risk with corticos- (studies) (GRADE)
placebo teroids
Improvement in sensory nerve function at 1 Study population RR 0.97 (0.65 to 71 ⊕⊕⊕⊝ -

year 1.45) (1 RCT) moderate 1
Assessed with: graded nylon filaments 585 per 1000 568 per 1000
(380 to 849)
Defined as a reduction by 3 or more points from
baseline
Improvement in motor nerve function at 1 The mean im- The mean improve- - 21 ⊕⊕⊝⊝ The MD slight-

year provement in ment in motor nerve (1 RCT) low 2 ly favoured the
Assessed with: MRC scale, inverted for the pur- motor nerve function at 1 year in placebo group,
poses of the trial (a more negative change score function at 1 the intervention group but not signifi-
indicated an improvement) year was -0.30 ± was 0.12 points high- cantly
1.6 points er (0.76 lower to 1.00
higher) (MD 0.12, 95%
CI -0.76 to 1.00)
Change in nerve pain and in nerve tenderness - - - - - -

at 1 year - not reported
4

Limitations in activities of daily living at 1 year - - - - - -
- not reported
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Limitations in participation at 1 year - not re- - - - - - -
ported
Adverse events Study population RR 1.87 (0.33 to 92 ⊕⊕⊕⊝ -

Assessed as adverse events requiring withdrawal 10.64) (1 RCT) moderate 1
of treatment 39 per 1000 73 per 1000 (13 to 417)
Better health.
Informed decisions.
Trusted evidence.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; MD: mean difference; MRC: Medical Research Council; RCT: randomised controlled trial; RR: risk ratio

High quality: We are very confident that the true effect lies close to that of the estimate of the effect
Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is sub-
stantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
1Small sample size.

2Very small sample size: 21 participants with motor nerve function impairment.


5

Informed decisions.

BACKGROUND is to exert a standardised pressure with a ballpoint pen. When

it is carefully used by trained staff, the ballpoint test can give
Description of the condition moderate to good results (Anderson 1999; Koelewijn 2003). Nerve
damage can result in loss of muscle strength and function. Muscle
Leprosy is a chronic infectious disease caused by the bacillus
strength is usually tested with the modified Medical Research
Mycobacterium leprae. Leprosy bacilli are probably spread through
Council (MRC) five-point scale (Brandsma 1981). Simpler three-
tiny droplets from the nose or mouth from infected and untreated
or four-point scales also exist, which are mainly used in the field
individuals. The disease develops when the immune system fails
(Lienhardt 1994).
to respond effectively to the antigens of the bacilli. The first sign
of leprosy is often a patch on the skin, but damage to peripheral Treatment
nerves may occur as well. Leprosy has various clinical forms,
depending on the response of the immune system. Some people Corticosteroids, especially prednisolone, are commonly used to
have only a few skin patches, and the number of bacilli is relatively treat severe reactions and nerve damage in leprosy, but convincing,
small. This is classified as paucibacillary (PB) leprosy. Other people high-quality evidence for their efficacy from any single study
have many skin patches and a high number of bacilli in their body, is lacking. Corticosteroids probably work by controlling acute
which is classified as multibacillary (MB) leprosy (ILEP 2001; WHO inflammation and relieving the associated pain (Britton 1998;
2006). Lockwood 2000). Common practice dictates that the earlier
corticosteroids are given after onset of nerve damage, the more
Leprosy infection can be effectively treated with a combination likely it is that permanent nerve function impairment will be
of several antibiotics, in the form of multidrug therapy (MDT). prevented (Becx-Bleumink 1990; Naafs 1996). The recommended
Since the introduction of MDT, the number of people affected by corticosteroid regimen for treating nerve damage starts with 40
leprosy has decreased substantially. In 2012, the prevalence was mg prednisolone daily and lasts for 12 weeks (WHO 1995). Studies
0.34 per 10,000 (almost 182,000 cases on treatment) worldwide. indicate that prolonged prednisolone treatment may be more
The number of newly detected cases registered in 2012 was effective in treating severe reactions and nerve damage (Becx-
approximately 233,000. About 14,000 of these new cases presented Bleumink 1990; Little 2001; Naafs 1979; Naafs 2003). Although
with visible deformity (grade 2 disability). The recorded global rate it appears to be a very effective drug, prednisolone has some
of grade 2 disability among new cases of leprosy was 0.25 per shortcomings. Long-term therapy can cause serious adverse
100,000 population in 2012 (WHO 2013). effects, such as peptic ulcer, cataract, or psychosis (Richardus
2003a; Sugumaran 1998; WHO 1998). Also, a considerable
Causes proportion of people treated for nerve damage do not benefit from
The body's immune response to the antigens of the leprosy bacilli corticosteroid treatment (Croft 2000; Lockwood 1993; Saunderson
may cause periods of inflammation in the skin and nerves, so- 2000; Schreuder 1998).
called reactions. Two types of reactions can occur: type 1 reaction,
Other therapies for improving nerve function and relieving nerve
or reversal reaction, and type 2 reaction, or erythema nodosum
pain, such as surgical nerve decompression and azathioprine, have
leprosum. Reactions can occur before, during, and after multidrug
been tested (Boucher 1999; Ebenezer 1996; Marlowe 2004; Pannikar
therapy, and are the main cause of nerve damage and impairment
1984). These interventions are beyond the scope of this review.
in leprosy (ILEP 2002; Lockwood 2005; WHO 1998). Nerve damage
may develop slowly and often goes unnoticed until the condition is Why it is important to do this review
advanced. It is often the symptoms of a reaction that force people
to seek help (Job 1989; Nicholls 2003). Corticosteroids are the drugs of choice for acute severe reactions
and nerve damage due to leprosy, but they have drawbacks. The
Impact long-term adverse effects of corticosteroids can be significant,
the long-term beneficial effects are uncertain, and the optimal
Leprosy is, most importantly, a disabling disease. The World Health
therapeutic regimen has not been established. Although this review
Organization estimates the number of people with disabilities
focusses on evidence from randomised controlled trials (RCTs),
due to leprosy at two to three million worldwide (WHO 2004).
only a few RCTs have been conducted in this area. We therefore
People affected by leprosy, especially those with visible deformities
considered the results in the light of non-randomised evidence in
and disabilities, fear discrimination and stigmatisation. These
the Discussion. This is an update of a review first published in 2007,
people can experience severe social and psychological problems
and previously updated in 2009 and 2011.
(Heijnders 2004; Leekassa 2004; Rafferty 2005).
Assessment of nerve function OBJECTIVES
Two tests are commonly used for testing sensory nerve function To assess the effects of corticosteroids on nerve damage in leprosy.
in people affected by leprosy. These tests work by pressing
or touching prespecified points on the palms and soles with METHODS
nylon filaments or with the tip of a ballpoint pen (Koelewijn
2003; Van Brakel 2003). The Semmes-Weinstein monofilament Criteria for considering studies for this review
test is a sensitive and repeatable method using standardised Types of studies
monofilaments to detect changes in sensory nerve function (Bell-
Krotoski 1990). The ballpoint pen test is widely used and accepted Randomised controlled trials (RCTs) and quasi-RCTs. Quasi-RCTs
in practice because it is simple, cheap, and available worldwide are trials in which allocation is partially systematic, such as
(Anderson 1999; Lienhardt 1994; Van Brakel 2003). One difficulty alternation, case record number, or birth date.

Informed decisions.

Types of participants 2. Change in nerve pain and in nerve tenderness at one year, as
determined and defined by the trial authors or according to
Anyone with leprosy, confirmed by appropriate clinical signs or
Pearson's Scale (Pearson 1982) (Table 4).
symptoms according to the Ridley 1966 or WHO 1998 classification
(Table 1) and leprosy-related nerve damage or severe leprosy type 3. Limitations in daily activities at one year, as measured with
1 reaction requiring corticosteroid treatment. We defined nerve leprosy-validated instruments (such as the Screening of Activity
damage or nerve function impairment (NFI) as clinically detectable Limitation and Safety Awareness (SALSA)) (SALSA 2007).
impairment of motor or sensory nerve function. Our definition 4. Limitations in participation at one year, as measured with
did not include impairment of nerve conduction that was only leprosy-validated instruments (such as the Participation Scale
detectable by electrophysiological means (Croft 1999). (Van Brakel 2006)).
5. Occurrence of adverse events.
Types of interventions
We created ‘Summary of findings’ tables, in which we planned to
Any corticosteroid treatment for nerve damage in leprosy.
include the following outcomes:
The comparators were no treatment, placebo, or a different
• Improvement in sensory nerve function at one year.
corticosteroid regimen. The protocol of this review stated that
we would include corticosteroids plus any other drug-related or • Improvement in motor nerve function at one year.
surgical intervention versus corticosteroids. • Change in nerve pain and in nerve tenderness at one year.
• Limitations in activities of daily living (ADL) at one year.
We excluded trials that compared corticosteroids plus a
• Limitations in participation at one year.
complementary therapy with corticosteroids, because they did not
allow assessment of the value of corticosteroids for treating nerve • Adverse events.
damage in leprosy, which is the subject of this review. We will
Search methods for identification of studies
consider such trials in future reviews of the relevant intervention
for treating nerve damage in leprosy. Electronic searches
Types of outcome measures We searched the Cochrane Neuromuscular Specialised Register

(16 June 2015), the Cochrane Central Register of Controlled
These are the outcomes of interest in included studies. We did not Trials (CENTRAL; 2015, Issue 5 in the Cochrane Library), MEDLINE
use reporting of these outcomes as eligibility criteria during study (January 1966 to June 2015), EMBASE (January 1980 to June
selection. 2015), CINAHL Plus (January 1937 to June 2015), and LILACS
(January 1982 to June 2015). The detailed search strategies are
Primary outcomes
in the appendices: Cochrane Neuromuscular Specialised Register,
1. Improvement in nerve function at one year. Appendix 1; CENTRAL, Appendix 2; MEDLINE, Appendix 3; EMBASE,
a. Sensory nerve function measured with graded nylon Appendix 4; LILACS, Appendix 5; and CINAHL Plus, Appendix 6.
filaments or a ballpoint pen, compared to baseline
measurement. In general, we considered improvement as Searching other resources
determined and defined by the original authors. We adapted We checked bibliographies of the studies identified and contacted
the scores as defined by Van Brakel et al. (Van Brakel 2005; trial authors to identify additional published or unpublished data.
Table 2). For testing with graded nylon filaments, sensory NFI We searched the Current Controlled Trials Register (ISRCTN registry;
was diagnosed if the monofilament threshold was increased www.controlled-trials.com), ClinicalTrials.gov (clinicaltrials.gov),
from normal by three or more points for any sensory nerve. and the World Health Organization International Clinical Trials
Normal thresholds used were 200 mg for the hand and 2 g for Registry Platform (ICTRP; www.who.int/ictrp/search/en/) using the
the foot. If the score for any nerve decreased by three or more search term 'leprosy' (January 2016). We applied no language
points from the baseline score, the nerve was considered as restriction when searching for studies.
improved. When a non-graded test was used, such as the
ballpoint pen test, a nerve was diagnosed as impaired if two Data collection and analysis
or more test sites did not feel the stimulus. Improvement
for any nerve was defined as two or more test sites feeling Selection of studies
the stimulus, compared to the baseline measurement (Van Two review authors (NvV and JHR) independently screened the
Brakel 2003). titles and abstracts of all the publications identified to examine
b. Motor nerve function assessed with the modified MRC whether studies were eligible, according to specified inclusion
grading scale (Brandsma 1981; Table 3). Improvement was criteria. The review team resolved any disagreements through
defined as at least one-point improvement in score for any discussion.
muscle compared to the initial score.
Data extraction and management
Secondary outcomes
Two review authors (NvV and JHR) independently extracted data
For this update, we revised our outcomes, retaining the first from the included studies onto a data extraction form. They
primary outcome above as our sole primary outcome, with resolved any discrepancies by discussion. If data were missing, the
secondary outcomes as follows: review authors contacted trial authors. The review authors were
not blinded to trial author, journal, or institution.
1. Improvement in nerve function at two years

Informed decisions.

Assessment of risk of bias in included studies RESULTS

Two review authors (NvV and JHR) independently assessed the
Description of studies
risk of bias in the included studies based on the following
criteria: random sequence allocation, concealment of allocation; The number of papers found by the new, current search strategies
blinding of participants and outcome assessors; loss to follow- were as follows: Cochrane Neuromuscular Specialised Register
up (incomplete outcome data); selective reporting; and other 17 (2 new papers), CENTRAL 12, MEDLINE 205 (42 new papers),
sources of bias (for example clear diagnosis, baseline differences), EMBASE 113 (36 new papers), LILACS 8 (6 new papers), and CINAHL
as described in the Cochrane Handbook for Systematic Reviews Plus 7.
of Interventions (Higgins 2011). In the event of disagreement, we
sought consensus by discussion. We identified 17 potentially relevant studies (in 19 papers), of
which we excluded 12 because they were either not randomised;
The review authors assessed each criterion as high, low, or unclear compared corticosteroids plus a complementary therapy versus
risk. If the report did not describe one of the criteria, we assessed it corticosteroids, or corticosteroids versus another therapy; or
as 'unclear'. We considered follow-up adequate if the loss to follow- focused on prevention of nerve damage. For a description of
up was less than 10%. excluded trials, see Characteristics of excluded studies. We did not
find any ongoing studies in our searches of trials registers.
Measures of treatment effect
We included five RCTs, with the following interventions:
We used the Cochrane statistical package, Review Manager 5
(RevMan) for statistical data analysis (RevMan 2014). The study 1. Corticosteroids versus placebo
results were not suitable for pooling, meaning that we were not able a. Treatment of mild sensory nerve function impairment (less
to calculate a weighted treatment effect. We expressed results as a than 6 months' duration) (Van Brakel 2003)
mean difference with a 95% confidence interval (CI) for continuous
b. Treatment of longstanding nerve function impairment (6 to
outcome measures and as a risk ratio with 95% CI for dichotomous
24 months' duration) (Richardus 2003)
outcomes. We analysed participants with NFI of less than 6 months'
duration and participants with longstanding impairment (6 to 24 2. High-dose corticosteroids versus low-dose corticosteroids
months' duration) separately. We expressed adverse effects as the versus short-regimen corticosteroids (see below and
proportion of participants with adverse events. It was not possible Characteristics of included studies for doses)
to perform tests for heterogeneity or sensitivity analysis due to a. Treatment of severe leprosy type 1 reactions (Rao 2006)
insufficient trials. We will perform such analyses, as specified in 3. High-dose prednisone versus low-dose prednisone (see below
our protocol (Van Veen 2005), should trials become available in the and Characteristics of included studies for doses)
future. a. Treatment of ulnar neuropathy (Garbino 2008)
4. Intravenous methylprednisolone and oral prednisolone versus
Adverse effects intravenous normal saline and oral prednisolone
In our Discussion, we considered adverse effects taking non- a. Treatment of leprosy type 1 reactions and nerve function
randomised literature into account, since randomised studies impairment, or both (Walker 2011)
rarely capture adverse events adequately.
For a full description of included trials, see Characteristics of
Economic issues included studies.
We considered the costs and cost-effectiveness of treatment if data Risk of bias in included studies
were available.
For a summary of the review authors' 'Risk of bias' assessments
for each included study, see Characteristics of included studies and
Figure 1.


Informed decisions.

Figure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation Incomplete outcome data
Sequence generation was random in all trials. We considered We considered three trials at low risk of bias with regard to
the allocation concealment adequate in all but one of the trials reporting of incomplete outcome data (based on follow-up and
(Garbino 2008), which we assessed as at unclear risk of bias. intention-to-treat analysis) (Garbino 2008; Richardus 2003; Walker
2011). We assessed two trials as at unclear risk of attrition bias:
Blinding Rao 2006 reported 19% loss to follow-up, Van Brakel 2003 had 11%
Participant, personnel, and outcome assessor blinding were loss to follow-up, and neither trial conducted an intention-to-treat
adequate in four trials. Garbino 2008 did not report blinding; we analysis.
assessed the risk of bias as unclear.
Selective reporting
None of the studies reported only selective outcomes.

Informed decisions.

Other potential sources of bias Secondary outcomes

None identified. Improvement in nerve function at two years
Outcomes The trial had a follow-up of one year from the start of treatment.
Two trials evaluated the primary outcomes. Richardus 2003 and Change in nerve pain and in nerve tenderness at one year
Van Brakel 2003 evaluated 'improvement in sensory nerve function Not measured.
one year after registration', and Richardus 2003 additionally
evaluated 'improvement in motor nerve function one year after Adverse events
registration'. Three trials evaluated the occurrence of adverse
Occurrence of one or more major adverse events, requiring
events (Richardus 2003; Van Brakel 2003; Walker 2011). None of withdrawal of treatment, within one year
the trials evaluated the secondary outcomes change in nerve pain
at one year, and limitations in activities of daily living and in Major adverse events were reported in two participants. One person
participation. was diagnosed with diabetes, and one with an infected ulcer. The
participant with diabetes was taking prednisolone. The participant
Effects of interventions with an infected ulcer was taking placebo. The difference between
the two groups was not significant (RR 0.83, 95% CI 0.05 to 12.77)
See: Summary of findings for the main comparison (Analysis 1.3). Also, the trialists recorded events requiring full-dose
Corticosteroids compared with placebo for treating nerve damage corticosteroids, which were a positive result on the ballpoint pen
(< 6 months' duration) in leprosy; Summary of findings 2 test, developing a type 1 reaction, or other events. Participants
Corticosteroids compared to placebo for treating nerve damage (6 experiencing such outcome events were taken out of the trial. In
to 24 months' duration) in leprosy the prednisolone group, 11 participants had an outcome event, and
Corticosteroids versus placebo for participants with mild in the control group, six participants had an outcome event. The
sensory nerve function impairment (NFI) of less than six difference between the groups was not statistically significant (RR
months' duration 0.66, 95% CI 0.27 to 1.59).
One trial compared prednisolone with placebo in participants with Corticosteroids versus placebo for participants with
mild sensory NFI (n = 84) (Van Brakel 2003). See Summary of longstanding NFI of 6 to 24 months' duration
findings for the main comparison. One trial compared corticosteroids and placebo in participants with
Primary outcomes longstanding NFI (Richardus 2003). See Summary of findings 2.
Improvement in sensory nerve function at one year Primary outcomes

Results at one year after the start of treatment were available Improvement in sensory nerve function at one year
for 41 participants in the prednisolone group and 34 participants Richardus 2003 compared prednisolone with placebo in
in the placebo group. Improvement was measured as either a participants with longstanding sensory NFI (n = 95). Results of
change score between baseline and end of follow-up or as the sensory nerve function at one year after the start of treatment
proportion of participants improved. Change in sensory score were available for 40 participants in the prednisolone group and
between 12 months from the start of treatment and registration was 49 participants in the placebo group. Of these 89 participants, 71
calculated. Sensory testing was done with five coloured, graded had sensory NFI only and 18 had had both sensory and motor NFI
monofilaments (200 mg, 2 g, 4 g, 10 g, and 300 g). For the ulnar at randomisation. Improvement was measured as either a change
nerve, the 200 mg, 2 g, 4 g, and 300 g filaments were used. For the score between baseline and end of follow-up or the presence of
posterior tibial nerve, the 2 g, 4 g, 10 g, and 300 g filaments were improvement. Changes in sensory score between 12 months from
used. Investigators tested six sites on the palm of the hand and four the start of treatment and registration were calculated. Sensory
sites on the sole of the foot. Table 2 shows the scoring method. testing was done following the same procedure as Van Brakel 2003.
Sensory improvement was defined as a reduction by three or more Sensory improvement was defined as a reduction by three or more
points from baseline to 12 months' follow-up. Mean difference points from baseline to 12 months' follow-up. MDs between the
(MD) between the baseline score and the score at 12 months' baseline score and the score at 12 months were compared for the
follow-up were compared for the two treatment groups. After 12 two treatment groups. After 12 months, the MD was -1.25 ± 1.66
months, the mean change was -2.68 ± 2.66 in the prednisolone in the prednisolone group and -1.67 ± 3.02 in the placebo group,
group and -3.00 ± 2.75 in the placebo group, both implying a mean indicating a mean improvement in both groups. The improvement
improvement. The improvement was slightly greater in the placebo was slightly greater in the placebo group, but the MD of 0.42 (95% CI
group, but the MD of 0.32 (95% CI -0.91 to 1.55) between the two -0.57 to 1.41) between the two groups was not significant (Analysis
groups was not significant (Analysis 1.1). The report also gave the 1.1). The proportion with sensory improvement after one year was
proportion of people with sensory improvement after one year. In also given for participants with only sensory impairment (n = 71). In
the prednisolone group, 33 out of 41 participants (80%) had sensory the prednisolone group, 17 out of 30 participants (57%) had sensory
improvement compared with 27 out of 34 participants (79%) in the improvement compared with 24 out of 41 participants (59%) in the
placebo group. The difference was not significant (risk ratio (RR) placebo group. The difference was not significant (RR 0.97, 95% CI
1.01, 95% CI 0.81 to 1.27) (Analysis 1.2). 0.65 to 1.45) (Analysis 1.2).
Improvement in motor nerve function at one year
Not measured.

Informed decisions.

Improvement in motor nerve function at one year • Low-dose: Prednisolone start at 30 mg/day and gradually
Richardus 2003 compared prednisolone with placebo in tapered thereafter with 5 mg for 2, 4, or 8 weeks until 5 months
participants with longstanding motor NFI (n = 21). Results of completed (total 2310 mg).
motor nerve function at one year after the start of treatment were • Short-regimen: Prednisolone start at 60 mg/day and gradually
available for 11 participants in the prednisolone group and 10 tapered thereafter with 20 mg or 10 mg for 2 weeks until 3
participants in the placebo group. Of these 21 participants, three months completed (total 2940 mg), plus 2 months of placebo.
had motor NFI only and 18 had both sensory and motor NFI.
This trial evaluated none of the outcome measures prespecified for
Improvement was measured as either a change score between
this review.
baseline and end of follow-up or as the proportion of participants
improved. Motor nerve function of the ulnar nerve was assessed The primary endpoint was the requirement for additional
with the modified MRC grading scale. The MRC scale was inverted corticosteroids during the 12-month trial period. A poor outcome
for the purposes of this trial. A score of two or more points was was defined as a failure to respond to treatment in terms of
considered as severe motor NFI. Change in motor score between 12 changes to skin lesions, nerve pain or tenderness, or nerve
months from the start of treatment and registration was calculated. function, or recurrences of skin or nerve lesions and needing extra
A negative change score was considered an improvement. After corticosteroids. At the end of the 12-month period, 41 out of 90
12 months, the MD was -0.18 ± 0.98 in the prednisolone group participants (46%) in the short-regimen group (2940 mg over three
and -0.30 ± 1.06 in the placebo group, both indicating a mean months) needed extra corticosteroids. In the group receiving a low
improvement. The improvement was slightly greater in the placebo dose of prednisolone (2310 mg over five months), this was 28 out
group, but the MD of 0.12 (95% CI -0.76 to 1.00) between the two of 91 (31%); and 21 out of 88 participants (24%) following a high-
groups was not significant (Analysis 1.4). The presence of motor dose prednisolone regimen (3500 mg over five months) required
improvement after one year was also given for participants with additional prednisolone. The difference between the high-dose
pure motor impairment (n = 3). In the prednisolone group, one out and low-dose five-month regimen was not significant (RR 0.78,
of one participant had motor improvement compared with zero out 95% CI 0.48 to 1.26, n = 179) (Analysis 2.1). The RR of needing
of two participants in the placebo group, but the difference was not additional corticosteroids was significantly less with the high-dose
significant (RR 4.50, 95% CI 0.32 to 63.94) (Analysis 1.5). five-month course than with the three-month course (RR 0.52, 95%
CI 0.34 to 0.81, n = 178) (Analysis 3.1). The RR of needing additional
Secondary outcomes
corticosteroids was just significantly less with the low-dose five-
Improvement in nerve function at two years month course than with the three-month course (RR 0.68, 95% CI
The trial had a follow-up of one year from the start of treatment. 0.46 to 0.99, n = 181) (Analysis 4.1).
Change in nerve pain and in nerve tenderness at one year Adverse events
These outcomes were not measured. No serious side effects of corticosteroids were reported in any
participant from the routine clinical examinations during the
Adverse events follow-up period.
Occurrence of one or more major adverse events requiring withdrawal
High-dose prednisone versus low-dose prednisone for
of treatment within one year
participants with ulnar neuropathy and type 1 or type 2
Five participants left the trial due to symptoms of possible major leprosy reaction
adverse events. Three were in the prednisolone group (diabetes,
One trial (n = 21) compared high-dose prednisone (commencing 2
infected ulcer, 'hypersensitivity' to the tablets), and the other two
mg/kg/day tapering over 6 months) versus low-dose prednisone
were in the placebo group (diabetes, peptic ulcer). The difference
(commencing 1 mg/kg/day tapering over 6 months) for participants
between the two groups was not significant (RR 1.87, 95% CI 0.33
with ulnar neuropathy and type 1 or type 2 leprosy reaction
to 10.64 among those with NFI of more than six months' duration)
(Garbino 2008). See Table 8.
(Analysis 1.3). Another 30 participants, 15 in each group, developed
events that required full-dose corticosteroid treatment (type 1 or This trial evaluated none of the outcome measures prespecified for
type 2 reactions, any signs of recent NFI). These participants were this review.
removed from the trial.
This trial evaluated clinical score, calculated as a summation of
High-dose corticosteroids versus low-dose corticosteroids visual analogue scale score (pain), nerve pain score, graded sensory
versus short-regimen corticosteroids for participants with testing score, and voluntary muscle testing score after six months.
severe type 1 reactions People with type 1 (n = 12) reaction or type 2 reaction (n = 9) were
One trial compared high-dose corticosteroids versus low-dose randomly allocated to either a steroid regimen starting with 2 mg/
corticosteriods versus short-regimen corticosteroids for severe type kg/day (experimental group, n = 12) or a steroid regimen starting
1 leprosy reactions (n = 181) (Rao 2006). See Table 5; Table 6; Table 7. with 1 mg/kg/day (control group, n = 9). Both regimens were
gradually tapered off during the six-month trial period if possible.
Doses were as follows: Nerve pain (visual analogue scale), nerve palpation (grade 0 to 5),
sensory nerve function (monofilaments), and motor nerve function
• High-dose: Prednisolone 60 mg/day and gradually tapered (MRC scale) were measured and summarised in a clinical score.
thereafter with 10 mg or 5 mg for 2 or 4 weeks until 5 months In addition, a neurophysiological evaluation (for example nerve
completed (total 3500 mg). conduction) was done. Results were reported at the end of the
six-month trial period, comparing experimental and control group
Informed decisions.

(type 1 and type 2 reactions) and type 1 versus type 2 reactions. Overall completeness and applicability of evidence
All ulnar nerves showed improved clinical scores at the end of six
months, but no significant differences were found, either between Five RCTs fulfilled the inclusion criteria for this review. The
experimental and control group or type 1 and type 2 reactions. interventions and outcomes were too heterogeneous to be entered
Improvement in neurophysiological parameters was significant in a meta-analysis. The numbers of participants included in the
during the first month of treatment in the experimental group, but trials were small and did not allow for subgroup analysis. The
this benefit had disappeared at the end of six months. variability between studies and the limitations in sample size made
it difficult to draw any robust conclusions.
Adverse events
The occurrence of adverse effects was not significantly higher in
Two participants developed adverse effects of major severity the corticosteroid groups compared to the placebo groups. There
during the trial period, both of them in the high-dose group: one was no statistically significant difference in adverse event rates
participant developed osteoporosis with collapse of the 10th dorsal between intravenous methylprednisolone with oral prednisolone
vertebra, and another developed hyperglycaemia and cataracts. and oral prednisolone alone. One meta-analysis, including 6602
participants, reviewed the adverse effects of corticosteroid
Intravenous methylprednisolone and oral prednisolone treatment compared to placebo treatment in randomised, double-
versus intravenous normal saline and oral prednisolone for blind, controlled trials. The review found that minor dermatologic
participants with type 1 reaction or new NFI of less than 6 adverse effects (for example moon face and acne), diabetes,
months' duration hypertension, and psychosis were reported significantly more
One trial (n = 42), reported in two papers, compared often in participants receiving steroids compared to participants
intravenous methylprednisolone followed by oral prednisolone in the placebo group. The occurrence of peptic ulcer did not
with intravenous normal saline and oral prednisolone (Walker differ significantly between groups and should not be considered
2011). See Table 9. a contraindication for corticosteroid treatment (Conn 1994). One
study reported on the occurrence of adverse events in the three
Changes in nerve function were measured, but the proportion TRIPOD trials. The study found that the relative risk of acne, fungal
of participants with improvement was not reported. Walker 2012 infections, and gastric pain was increased in the corticosteroid
reported the results of gene and protein expression of toll-like group. Most of these events were reversible and did not require
receptors in the cutaneous lesions of leprosy type 1 reactions at the discontinuation of treatment or removal from the trials. No
onset of reaction and during systemic corticosteroid therapy. We increased risk of major adverse events such as hypertension,
did not consider this outcome measure important for this review. diabetes, cataract, and psychosis was found in the corticosteroid
group compared to the placebo group. With strict procedures
Adverse events and good surveillance, standardised corticosteroid therapy can be
The primary outcome measure in Walker 2011 was the frequency safely administered (Conn 1994; Richardus 2003; Richardus 2003a).
of adverse events during the study period (337 days). Twenty-three
participants experienced at least one adverse event, 12 (54.5%)
Quality of the evidence
in the prednisolone-alone arm and 11 (55%) in the prednisolone We considered the evidence quality to be moderate to low, mainly
with methylprednisolone arm. There was no statistically significant due to the small sample sizes of the trials.
difference in adverse event rate between the two treatment arms
(Analysis 5.1; Table 9). Two participants (one from each arm of the Potential biases in the review process
study) experienced a major adverse event; one was diagnosed with
The search process was elaborate, and to our knowledge no other
glaucoma and the other with infected neuropathic ulcers.
RCTs were available for this review.
DISCUSSION
Agreements and disagreements with other studies or
Summary of main results reviews
Corticosteroids are commonly used in the of management of Several non-randomised studies have examined the effect of
acute nerve damage in leprosy, but the long-term effect and corticosteroids for treating severe reactions and nerve damage
optimal regimen of corticosteroids remain uncertain. None of in leprosy. The response to corticosteroid treatment seems to
the trials found a significant difference in improvement in nerve depend on the severity and duration of nerve function impairment
function between treatment and control groups 12 months after (NFI) before the start of treatment. One study found that 35%
the start of treatment. We did not explore earlier time points of people with leprosy with complete anaesthesia and 67% with
in our prespecified outcome measures. However, one small well- moderate sensory impairment improved to good function three
performed study of moderate quality and at low risk of bias months after the start of corticosteroid treatment. For people
reported a small difference in monofilament threshold perception with complete motor paralysis or moderate motor impairment,
at 4 months in patients with short-term (less than 6 months 11% and 55%, respectively, recovered to good function (Van
duration) disease, which was not sustained to later time points. Brakel 1996). The included RCT evaluating the treatment mild
None of the trials included quality of life measures or cost- sensory impairment found that a significantly higher proportion
effectiveness calculations. of participants improved in the prednisolone group compared
to the placebo group after four months, although the difference
disappeared by the six-month follow-up (Van Brakel 2003). Another
study found that it may take a long time to achieve full recovery
of chronic or recurrent NFI, much longer than the duration of

Informed decisions.

a standard steroid course (Saunderson 2000). Recovery of nerve One RCT examined the effect of prophylactic use of steroids in 636
function loss seems to be more likely when the duration of NFI people with newly diagnosed multibacillary leprosy (Smith 2004).
is less than six months (Becx-Bleumink 1990; Britton 1998). To This study showed that a low-dose prophylactic steroid regimen
illustrate, data from Ethiopia showed that people with NFI for less reduced the risk of NFI at the end of four months (RR 3.9, 95% CI
than six months who were treated with steroids had full recovery in 2.1 to 7.3), but the effect was not sustained at one year (RR 1.3,
50 out of 57 nerves (88%), while in people with recurrent or chronic 95% CI 0.9 to 1.8). Repeat use of steroid prophylaxis for a longer
NFI, only 20 out of 39 nerves (51%) had fully recovered after up period than four months may sustain the benefit, but this needs to
to 10 years of treatment (Saunderson 2000). This is in line with be examined further. A non-randomised follow-up study evaluated
the included RCT evaluating the treatment longstanding NFI, which the effect of the combined use of steroids and multidrug therapy
found that 19 out of 41 nerves (46%) treated with prednisolone (MDT) in preventing nerve damage in participants with pure neural
improved (Richardus 2003). However, even in the placebo group, (PN) leprosy (n = 24) (Jardim 2007). People with PN leprosy present
25 out of 51 nerves (49%) showed spontaneous improvement with nerve damage or enlarged peripheral nerves but without
after 12 months. Other studies have also reported spontaneous having any sign of skin manifestation or skin patches. Participants
nerve function improvement in untreated individuals (Croft 2000; received a paucibacillary MDT regimen for six months plus a daily
Saunderson 2000; Schreuder 1998). morning dose of 1 mg/kg of prednisolone for one month followed
by a progressive 10 mg monthly reduction over the remaining
If one assumes some therapeutic effect of steroids (not shown five months. Assessment of sensory nerve function, motor nerve
in this review), the optimal corticosteroid regimen has not function, and nerve pain was done with monofilaments, MRC
been established. Recommendations about the optimal dose and scale, and visual analogue scale, respectively, at diagnosis and
duration of steroid therapy have changed over time (Naafs 2003; 12 months after the start of MDT. One out of 20 participants
Pearson 1981). The principles of a steroid therapy are to start with (5%) with initial sensory NFI and 5 out of 21 participants (24%)
a dose that is sufficient to control the inflammation rapidly, then to with initial motor NFI showed improvement 12 months after the
taper off until the reaction has settled. The ideal would be a steroid start of MDT. Relief of neural pain was reported in four out of
course adjusted and tailored to the individual's situation, but this nine participants (44%). Nerve conduction parameters were also
may only be possible in referral centres (Rose 1991). Currently, measured, and a significant reduction of nerve conduction block
the World Health Organization recommends a standard 12-week was found. The study authors indicate the need for a double-
course of prednisolone, which can be safely used in the field (WHO blind, placebo-controlled study for further evaluation of steroids as
1995). Other studies have suggested that a prolonged regimen prophylactic drugs.
might be more beneficial (Little 2001; Naafs 1979; Naafs 2003; Rose
1991). One small retrospective study compared a short-term steroid An alternative therapeutic approach for treating nerve damage
treatment (2 months) with a prolonged steroid treatment (3 to in leprosy has been surgical decompression of acutely inflamed
18 months) for type 1 reaction in people with borderline leprosy. nerves. This approach is the subject of another Cochrane review
The study found that the longer treatment gave better results on (Van Veen 2009).
improving motor nerve function than the two-month treatment
and did not increase the risk of adverse events. The critical dose to There is an ongoing search for new therapies for nerve damage
control a reaction after the initial period was considered to be 15 in leprosy because steroids are not always effective, can cause
mg to 20 mg daily (Naafs 1979). One study examined the effects of serious adverse effects, and because their long-term effect is
prednisolone treatment on the cellularity and cytokine profiles of unclear. One recent quasi-RCT compared an eight-week course of
leprosy skin type 1 reactions. The results showed that prednisolone prednisolone combined with azathioprine with a 12-week course
treatment decreased cytokine levels significantly only after 28 of prednisolone alone for treating severe type 1 reactions (Marlowe
days from the start of treatment. Some people continued to have 2004). The trial did not find a significant difference between the
cytokine production for one to six months. This study illustrates two treatment groups in clinical severity scores, but the study
the slow response to steroid therapy and continuing activity for was limited in size (n = 40) and unlikely to have been long
several months (Little 2001). While these non-randomised studies enough for azathioprine to work. Therapies that are used for other
already suggested the benefits of a prolonged steroid course, the immune-mediated conditions, such as ciclosporin or combinations
included RCT comparing three corticosteroid regimens confirms of immunosuppressants, may be promising. It is plausible that
this in reporting that a longer duration of prednisolone treatment these therapies could be effective for treating nerve damage in
requires less additional steroids to control type 1 reactions than a leprosy, but evidence from RCTs is lacking (Lockwood 2000). Two
short course of prednisolone (Rao 2006). studies, one comparing ciclosporin with prednisolone and one
compariing azathioprine with prednisolone, have been undertaken
According to other authorities, a substantial proportion of and will soon be published (Lambert 2014; Lockwood 2014).
individuals treated for nerve damage do not respond to
corticosteroids. The overall nerve function improvement levels vary A non-randomised follow-up study assessed the effects of
between approximately 60% and 80% after steroid therapy (Croft ciclosporin treatment in 33 Ethiopian and 10 Nepali people with
2000). Croft 2000 reported that 27 out of 83 treated nerves with severe type 1 leprosy reactions (Marlowe 2007). Participants
motor impairment (33%) and 53 out of 166 treated nerves with initially received ciclosporin 5 mg/kg together with 40 mg oral
sensory impairment (32%) did not improve or had deteriorated 12 prednisolone for the first five days. Thereafter, participants received
months after the start of treatment. In a study in Thailand, 27 out of only ciclosporin for 12 weeks. This study used the clinical severity
77 people with leprosy who were treated with prednisolone (35%) score as defined by Marlowe et al. (Marlowe 2004). The study
showed no improvement or a worsening of NFI (Schreuder 1998). found that among participants with acute NFI, 5 out of 16
(31%) had improved sensory scores and 9 out of 18 (50%) had
improved voluntary muscle testing scores whilst on treatment.

Informed decisions.

One participant maintained the sensory NFI, and five participants corticosteroid regimens do not appear to be more harmful
maintained motor NFI at 12 weeks after stopping ciclosporin. In than placebo treatment based on the moderate-quality evidence
participants with chronic NFI, 13 out of 21 (62%) had improved included here, despite known adverse effects of corticosteroids.
sensory scores, and 10 out of 20 (50%) had improved voluntary
muscle testing scores. Six participants maintained the sensory Implications for research
nerve function improvement, and four participants maintained
Further research is needed to establish optimal corticosteroid
motor nerve function improvement at 12 weeks after stopping
regimens, in combination with other therapies, for long-term
ciclosporin. Nerve pain and tenderness scores improved in 21 out
effectiveness and safety. Future trials should address non-clinical
of 41 participants (51%). The study reported jaundice (n = 1), raised
aspects, such as costs and impact on quality of life, which are highly
serum creatinine levels (n = 2), loss of appetite (n = 1), indigestion,
relevant indicators for both policymakers and people with leprosy.
dizziness, and epigastric pain (n = 1), and hypertension (n = 3) as
side effects of ciclosporin treatment. The trial authors suggest that ACKNOWLEDGEMENTS
ciclosporin monotherapy may be an effective treatment for severe
type 1 reactions, with few adverse effects. We would like to thank Dr AM Anderson and Dr JA Garbino for
providing additional information and Cochrane Neuromuscular
AUTHORS' CONCLUSIONS for advice and help. The Trials Search Co-ordinator of Cochrane
Neuromuscular, Angela Gunn, developed search strategies and ran
Implications for practice database searches.
The mainstay for treating nerve damage in leprosy is
This project was supported by the National Institute for Health
corticosteroids. We did not find robust evidence to support
Research (NIHR) via Cochrane Infrastructure funding to Cochrane
the long-term effectiveness of corticosteroids in improving
Neuromuscular. The views and opinions expressed therein are
nerve function. The optimal corticosteroid regimen is unclear
those of the review authors and do not necessarily reflect those of
and unsupported by evidence from RCTs, but a five-month
the Systematic Reviews Programme, NIHR, National Health Service
corticosteroid regimen appears to be more beneficial than
(NHS), or the Department of Health. Cochrane Neuromuscular is
a standard three-month corticosteroid regimen in terms of
also supported by the MRC Centre for Neuromuscular Diseases.
treatment response (need for additional corticosteroids). Standard

Informed decisions.

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Informed decisions.

References to other published versions of this review Van Veen 2007

Van Veen 2005 Van Veen NHJ, Nicholls PG, Smith WCS, Richardus JH.
Corticosteroids for treating nerve damage in leprosy.
Van Veen NHJ, Meima A, Nicholls PG, Smith WCS, Richardus JH.
Cochrane Database of Systematic Reviews 2007, Issue 2. [DOI:
Corticosteroid interventions for treating nerve damage in
10.1002/14651858.CD005491.pub2]
leprosy. Cochrane Database of Systematic Reviews 2005, Issue 4.
[DOI: 10.1002/14651858.CD005491]
* Indicates the major publication for the study

CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]

Garbino 2008
Methods Randomised, parallel-group trial
Participants 21 people with leprosy with ulnar neuropathy due to type 1 or type 2 leprosy reaction
Unit of randomisation: person
Unit of analysis: person or nerve
People randomised: 21 participants with 34 ulnar nerves
People analysed: 21 (a: 12, b: 9)
Interventions (a) Prednisone start at 2 mg/kg/day and thereafter gradually tapered until 6 months completed
(b) Prednisone start at 1 mg/kg/day and thereafter gradually tapered until 6 months completed
Outcomes Clinical score: summation of the results of VAS (pain), nerve pain, graded sensory testing, and voluntary
muscle testing at 6 months
Funding Not reported
Conflicts of interest Not reported
Notes Study conducted in Brazil
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Low risk Randomisation: 2 random sequences were created by throwing a coin
tion (selection bias)
Allocation concealment Unclear risk Not reported if allocation sequence was adequately concealed
(selection bias)
Blinding of participants Unclear risk Blinding not reported

and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Blinding not reported

sessment (detection bias)
All outcomes
Incomplete outcome data Low risk No loss to follow-up

(attrition bias)
All outcomes

Informed decisions.

Garbino 2008 (Continued)
Selective reporting (re- Low risk No selective reporting
porting bias)
Other bias Low risk None identified

Rao 2006
Methods Randomised, double-blind, parallel-group trial
Participants 334 people with leprosy with severe type 1 reactions requiring steroid treatment
Unit of analysis: person
People randomised: 334
People analysed: 269 (a: 88, b: 91, c: 90)
Interventions (a) Prednisolone start at 60 mg/day and thereafter gradually tapered with 10 mg or 5 mg for 2 or 4
weeks until 5 months completed (total 3500 mg)
(b) Prednisolone start at 30 mg/day and thereafter gradually tapered with 5 mg for 2, 4, or 8 weeks un-
til 5 months completed (total 2310 mg)
(c) Prednisolone start at 60 mg/day and thereafter gradually tapered with 20 mg or 10 mg for 2 weeks
until 3 months completed (total 2940 mg) plus 2 months of placebo
Outcomes Requirement for additional corticosteroids during the 12-month trial period
Funding The Leprosy Mission International provided financial support for this trial
Conflicts of interest None of the authors has any competing interest
Notes Multicentre
Conducted in 6 centres in India
Risk of bias
Random sequence genera- Low risk Externally controlled computer randomisation

Allocation concealment Low risk Treatments externally assigned

(selection bias)
Blinding of participants Low risk The 3 regimens were presented in blister calendar packs containing the stip-
and personnel (perfor- ulated doses for 28 days. Each blister pack contained identical-looking white
mance bias) tablets whatever the dose of prednisolone or placebo
All outcomes
Blinding of outcome as- Low risk Assessors unaware of treatment assignment

All outcomes
Incomplete outcome data Unclear risk 19.5% loss to follow-up, no differences among the 3 regimens. Reasons for loss
(attrition bias) to follow-up not reported
All outcomes

Informed decisions.

Rao 2006 (Continued)
Selective reporting (re- Low risk Only clinical outcome, no functional outcomes
porting bias)
Other bias Low risk Diagnosis and classification according to internationally accepted criteria of
the WHO. No baseline differences between the 2 groups

Richardus 2003
Methods Randomised, double-blind, placebo-controlled, parallel-group trial
Double-blind
Placebo-controlled
Participants 95 people with confirmed MB leprosy diagnosis having untreated sensory or motor impairment of the
ulnar or posterior tibial nerve of more than 6 months' up to 24 months' duration
Unit of analysis: ulnar or posterior tibial nerve. Of participants with bilateral NFI, the scores of the least
affected limb were used in the analysis. If both limbs were equally affected, then the scores of the right
side were used in the analysis
Nerves randomised: 95
Nerves analysed: 92 (a: 41, b: 51)
Interventions (a) Prednisolone start at 40 mg/day and thereafter gradually tapered with 5 mg for 2 weeks until 16
weeks completed (total 2520 mg)
(b) Placebo, equivalent number of tablets for 16 weeks
Outcomes Change in:
1. Sensory score after 1 year, using 5 graded monofilaments

2. Voluntary muscle testing score after 1 year, using modified MRC 5-point scale
3. Occurrence of major adverse events
Funding Trial was sponsored by Lepra UK, the Leprosy Mission International, American Leprosy Missions, the
University of Aberdeen (UK), and the International Nepal Fellowship
Notes Multicentre
Conducted in Nepal and Bangladesh
TRIPOD 3
Risk of bias


(selection bias)
Blinding of participants Low risk Treatment regimens similar, and the placebo tablets were manufactured to be
and personnel (perfor- the same size, shape, and colour as the prednisolone tablets
mance bias)
All outcomes

Informed decisions.

Richardus 2003 (Continued)
All outcomes
Incomplete outcome data Low risk Only 3% loss to follow-up

(attrition bias)
All outcomes
Selective reporting (re- Low risk Primary outcomes, sensory and motor NFI after 1 year, have been measured
porting bias) and reported

Van Brakel 2003
Participants 84 people with confirmed MB leprosy having sensory impairment of the ulnar or posterior tibial nerve
of less than 6 months' duration, as measured with the Semmes-Weinstein test. The ballpoint pen test
had to be normal
Unit of analysis: ulnar or posterior tibial nerve. Of participants with bilateral NFI, the scores of the most
affected limb were used in the analysis. If both limbs were equally affected, then the scores of the right
side were used in the analysis
Nerves randomised: 84
Nerves analysed: 75 (a: 41, b: 34)
Interventions (a) Prednisolone start at 40 mg/day and thereafter gradually tapered with 5 mg for 2 weeks until 16
weeks completed (total 2520 mg)
(b) Placebo, equivalent number of tablets for 16 weeks
Outcomes Change in:
1. Sensory score after 1 year, using 5 graded monofilaments

2. Occurrence of major adverse events
Funding Trial was sponsored by Lepra UK, the Leprosy Mission International, American Leprosy Missions, the
University of Aberdeen (UK), and the International Nepal Fellowship
Notes Multicentre
Conducted in Nepal and Bangladesh
TRIPOD 2
Risk of bias


Informed decisions.

Van Brakel 2003 (Continued)

(selection bias)
Blinding of participants Low risk Treatment regimens were similar, and the placebo tablets were manufactured
and personnel (perfor- to be the same size, shape, and colour as the prednisolone tablets
mance bias)
All outcomes

All outcomes
Incomplete outcome data Unclear risk 11% loss to follow-up. Reasons for loss to follow-up not reported
(attrition bias)
All outcomes
Selective reporting (re- Low risk Primary outcome, sensory NFI after 1 year, has been measured and reported
porting bias)

Walker 2011
Participants 42 people diagnosed with leprosy with clinical evidence of type 1 reaction of less than 6 months' dura-
tion or with new NFI of less than 6 months' duration without inflammation of skin lesions (if present)
Unit of analysis: person
People analysed: 42 (a: 20, b: 22)
Interventions (a) 1 g methylprednisolone in normal saline given as an IV infusion and 8 dummy tablets identical in ap-
pearance to prednisolone tablets daily for the first 3 days of the trial. Thereafter participants in both
groups received same reducing course of prednisolone*. A participant allocated to the methylpred-
nisolone group received a total dose of corticosteroid equivalent to 6.15 g of prednisolone
(b) 40 mg (8 tablets) of prednisolone and an identical-appearing IV infusion that contained only nor-
mal saline daily for the first 3 days of the trial. Thereafter participants in both groups received same re-
ducing course of prednisolone*. Participants in the prednisolone-alone group received 2.52 g of pred-
nisolone in total
* This course was prednisolone 40 mg daily from day 4 to day 14 of the study. The amount of pred-
nisolone was then reduced to 35 mg daily for the next 14 days and then by a further 5 mg daily every 14
days to 0.
All participants enrolled into the study received albendazole 400 mg daily for the first 3 days of the trial
and famotidine 40 mg daily whilst they were receiving corticosteroids
Outcomes Primary outcome measure:
1. frequency of adverse events
Secondary outcome measures:
1. change in clinical severity score

Informed decisions.

Walker 2011 (Continued)
2. change in clinical NFI
3. time to next steroid-requiring reactional episode or acute NFI
4. amount of supplementary prednisolone required in addition to the reducing 16-week regimen
The investigators reported gene and protein expression of toll-like receptors (TLR) 2 and TLR4 in skin
biopsies in a second paper (Walker 2012)
Funding "Grants from LEPRA, the American Leprosy Mission, the Special Trustees of the Hospital for Tropical
Diseases, London, and the Geoffrey Dowling Fellowship of the British Association of Dermatologists"
Conflicts of interest "None declared"
Notes Conducted in Nepal
Risk of bias
Random sequence genera- Low risk Block randomisation in groups of 4 using a random number table
Allocation concealment Low risk A standard envelope system was used. The envelopes were pre-packed in Lon-
(selection bias) don by a person who had no other involvement in the study. The allocation
procedure was decentralised and operated solely by a person who kept a sep-
arate record of the allocation and who had no contact with the study partici-
pants
Blinding of participants Low risk All study participants, physicians, ward staff, and other assessors (physio-tech-
and personnel (perfor- nicians) were blinded to the allocation
mance bias)
All outcomes
Blinding of outcome as- Low risk Assessors were blinded to the allocation
All outcomes
Incomplete outcome data Low risk An intention-to-treat analysis was used

(attrition bias)
All outcomes
Selective reporting (re- Low risk No selective reporting

porting bias)
Other bias Low risk No other bias identified
IV: intravenous
MB: multibacillary
MRC: Medical Research Council
NFI: nerve function impairment
VAS: visual analogue scale
WHO: World Health Organization

Characteristics of excluded studies [ordered by study ID]


Informed decisions.

Study Reason for exclusion
Boucher 1999 Comparing surgical decompression in addition to corticosteroids versus corticosteroids
Croft 2000 Case-control study. No randomisation procedure
Dandapat 1991 Comparing neurolysis versus neurolysis plus corticosteroid injection
Ebenezer 1996 Comparing surgical decompression in addition to corticosteroids versus corticosteroids
Jardim 2007 Steroid prophylaxis for prevention of nerve function impairment in leprosy. No randomisation pro-
cedure
Lambert 2014 Trial comparing ciclosporin with prednisolone
Lockwood 2014 Trial comparing azathioprine with prednisolone
Marlowe 2004 Comparing azathioprine in combination with corticosteroids versus corticosteroids
Marlowe 2007 Open trial. No randomisation procedure
Pannikar 1984 Comparing surgical decompression in addition to corticosteroids versus corticosteroids
Smith 2004 Steroid prophylaxis for prevention of nerve function impairment in leprosy
Wilder-Smith 1997 Case-control study. No randomisation procedure

DATA AND ANALYSES

Comparison 1. Corticosteroids versus placebo
Outcome or subgroup title No. of studies No. of partici- Statistical method Effect size
pants
1 Improvement in sensory score after 2 Mean Difference (IV, Fixed, Subtotals only
one year 95% CI)
1.1 NFI of less than six months' dura- 1 75 Mean Difference (IV, Fixed, 0.32 [-0.91, 1.55]
tion 95% CI)
1.2 NFI of more than six months' du- 1 89 Mean Difference (IV, Fixed, 0.42 [-0.57, 1.41]
ration 95% CI)
2 Proportion with sensory improve- 2 Risk Ratio (M-H, Fixed, 95% Subtotals only
ment after one year CI)
2.1 NFI of less than six months' dura- 1 75 Risk Ratio (M-H, Fixed, 95% 1.01 [0.81, 1.27]
tion CI)
2.2 NFI of more than six months' du- 1 71 Risk Ratio (M-H, Fixed, 95% 0.97 [0.65, 1.45]
ration CI)

Informed decisions.

pants
3 Proportion with serious adverse 2 Risk Ratio (M-H, Fixed, 95% Subtotals only
events CI)
3.1 NFI of less than six months' dura- 1 75 Risk Ratio (M-H, Fixed, 95% 0.83 [0.05, 12.77]
tion CI)
ration CI)
4 Improvement in motor score after 1 Mean Difference (IV, Fixed, Subtotals only
one year 95% CI)
4.1 NFI of more than six months' du- 1 21 Mean Difference (IV, Fixed, 0.12 [-0.76, 1.00]
ration 95% CI)
5 Proportion with motor improve- 1 Risk Ratio (M-H, Fixed, 95% Subtotals only
ment after one year CI)
ration CI)

Analysis 1.1. Comparison 1 Corticosteroids versus placebo, Outcome 1 Improvement in sensory score after one year.
Study or subgroup Treatment Control Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
1.1.1 NFI of less than six months' duration
Van Brakel 2003 41 -2.7 (2.7) 34 -3 (2.8) 100% 0.32[-0.91,1.55]
Subtotal *** 41 34 100% 0.32[-0.91,1.55]
Heterogeneity: Not applicable
Test for overall effect: Z=0.51(P=0.61)

1.1.2 NFI of more than six months' duration
Richardus 2003 40 -1.2 (1.7) 49 -1.7 (3) 100% 0.42[-0.57,1.41]
Subtotal *** 40 49 100% 0.42[-0.57,1.41]
Test for subgroup differences: Chi2=0.02, df=1 (P=0.9), I2=0%
Favours treatment -10 -5 0 5 10 Favours control

Analysis 1.2. Comparison 1 Corticosteroids versus placebo,
Outcome 2 Proportion with sensory improvement after one year.
Study or subgroup Treatment Control Risk Ratio Weight Risk Ratio
n/N n/N M-H, Fixed, 95% CI M-H, Fixed, 95% CI
Van Brakel 2003 33/41 27/34 100% 1.01[0.81,1.27]
Subtotal (95% CI) 41 34 100% 1.01[0.81,1.27]
Favours control 0.1 0.2 0.5 1 2 5 10 Favours treatment

Informed decisions.


Total events: 33 (Treatment), 27 (Control)

Richardus 2003 17/30 24/41 100% 0.97[0.65,1.45]
Subtotal (95% CI) 30 41 100% 0.97[0.65,1.45]
Heterogeneity: Tau2=0; Chi2=0, df=0(P<0.0001); I2=100%
Favours control 0.1 0.2 0.5 1 2 5 10 Favours treatment

Analysis 1.3. Comparison 1 Corticosteroids versus placebo, Outcome 3 Proportion with serious adverse events.
Study or subgroup Favours Control Risk Ratio Weight Risk Ratio
treatment
Van Brakel 2003 1/41 1/34 100% 0.83[0.05,12.77]
Subtotal (95% CI) 41 34 100% 0.83[0.05,12.77]
Total events: 1 (Favours treatment), 1 (Control)

Richardus 2003 3/41 2/51 100% 1.87[0.33,10.64]
Subtotal (95% CI) 41 51 100% 1.87[0.33,10.64]
Total events: 3 (Favours treatment), 2 (Control)
Test for subgroup differences: Chi2=0.24, df=1 (P=0.62), I2=0%
Favours treatment 0.02 0.1 1 10 50 Favours control

Analysis 1.4. Comparison 1 Corticosteroids versus placebo, Outcome 4 Improvement in motor score after one year.
Study or subgroup Treatment Control Mean Difference Weight Mean Difference
N Mean(SD) N Mean(SD) Fixed, 95% CI Fixed, 95% CI
Richardus 2003 11 -0.2 (1) 10 -0.3 (1.1) 100% 0.12[-0.76,1]
Subtotal *** 11 10 100% 0.12[-0.76,1]
Favours treatment -10 -5 0 5 10 Favours control


Informed decisions.

Analysis 1.5. Comparison 1 Corticosteroids versus placebo,

Outcome 5 Proportion with motor improvement after one year.
Richardus 2003 1/1 0/2 100% 4.5[0.32,63.94]
Subtotal (95% CI) 1 2 100% 4.5[0.32,63.94]
Favours control 0.01 0.1 1 10 100 Favours treatment

Comparison 2. High-dose versus low-dose five-month course corticosteroids
pants
1 Proportion needing additional corticos- 1 179 Risk Ratio (M-H, Fixed, 0.78 [0.48, 1.26]
teroids during 12 months 95% CI)

Analysis 2.1. Comparison 2 High-dose versus low-dose five-month course corticosteroids,
Outcome 1 Proportion needing additional corticosteroids during 12 months.
Study or subgroup Favours Low dose Risk Ratio Weight Risk Ratio
high dose
Rao 2006 21/88 28/91 100% 0.78[0.48,1.26]

Total (95% CI) 88 91 100% 0.78[0.48,1.26]
Total events: 21 (Favours high dose), 28 (Low dose)
Favours high dose 0.1 0.2 0.5 1 2 5 10 Favours low dose

Comparison 3. High-dose five-month versus three-month course corticosteroids
pants


Informed decisions.

Analysis 3.1. Comparison 3 High-dose five-month versus three-month course

corticosteroids, Outcome 1 Proportion needing additional corticosteroids during 12 months.
Study or subgroup Favours Short course Risk Ratio Weight Risk Ratio
high dose
Rao 2006 21/88 41/90 100% 0.52[0.34,0.81]

Total (95% CI) 88 90 100% 0.52[0.34,0.81]
Total events: 21 (Favours high dose), 41 (Short course)
Test for overall effect: Z=2.91(P=0)
Favours high dose 0.1 0.2 0.5 1 2 5 10 Favours short course

Comparison 4. Low-dose versus short-course corticosteroids
pants

Analysis 4.1. Comparison 4 Low-dose versus short-course corticosteroids,
Outcome 1 Proportion needing additional corticosteroids during 12 months.
Study or subgroup Low dose Short course Risk Ratio Weight Risk Ratio
Rao 2006 28/91 41/90 100% 0.68[0.46,0.99]

Total (95% CI) 91 90 100% 0.68[0.46,0.99]
Total events: 28 (Low dose), 41 (Short course)
Favours low dose 0.1 0.2 0.5 1 2 5 10 Favours short course

Comparison 5. Intravenous methylprednisolone and oral prednisolone versus intravenous normal saline and oral
prednisolone
pants
1 Adverse events 1 42 Risk Ratio (M-H, Fixed, 95% CI) 1.01 [0.58, 1.75]


Informed decisions.

Analysis 5.1. Comparison 5 Intravenous methylprednisolone and oral prednisolone

versus intravenous normal saline and oral prednisolone, Outcome 1 Adverse events.
Study or subgroup Methylpred- Saline Risk Ratio Weight Risk Ratio
nisolone
Walker 2011 11/20 12/22 100% 1.01[0.58,1.75]

Total (95% CI) 20 22 100% 1.01[0.58,1.75]
Total events: 11 (Methylprednisolone), 12 (Saline)
Favours MP 0.01 0.1 1 10 100 Favours saline

ADDITIONAL TABLES

Table 1. Leprosy classification - Ridley-Jopling WHO 1998
Ridley-Jopling WHO
TT: tuberculoid leprosy PB: paucibacillary leprosy
BT: borderline tuberculoid leprosy PB
BB: borderline leprosy MB: multibacillary leprosy
BL: borderline lepromatous leprosy MB
LL: lepromatous leprosy MB

Table 2. Sensory scoring system - Van Brakel et al.
Colour Approximate force Score for hand Score for foot
Blue filament felt 200 mg 0
Purple filament felt 2g 1 0
Red filament felt 4g 2 1
Orange filament felt 10 g 3 2
Pink filament felt 300 g 4 3
Pink filament not felt - 5 4

Table 3. Modified MRC scale - Brandsma 1981
Grade Definition

Informed decisions.

Table 3. Modified MRC scale - Brandsma 1981 (Continued)

5 Full range of movement of the joint on which the muscle or muscle group is acting. Normal resis-
tance can be given
4 Full range of movement but less than normal resistance
3 Full range of movement but no resistance
2 Partial range of movement with no resistance
1 Perceptible contraction of the muscle(s) not resulting in joint movement
0 Complete paralysis
MRC: Medical Research Council

Table 4. Scoring system for nerve pain and tenderness - Pearson
Score Grade
Nerve pain
3 Absent
2 Mild (only aware intermittently and does not limit activity)
1 Moderate (sleep disturbed, activities diminished, work efficiency diminished)
0 Severe (incapacitating)
Nerve tenderness
3 Absent
2 Mild (absent if person's attention is distracted)
1 Moderate (present if attention is distracted)
0 Severe (very tender and person withdraws the arm forcibly)

Table 5. High-dose corticosteroids compared to low-dose corticosteroids for treating nerve damage in leprosy (5-
month regimens)
High-dose corticosteroids compared to low-dose corticosteroids for treating nerve damage in leprosy (5-month regimens)
Patient or population: people with nerve damage in leprosy (severe type 1 leprosy reaction)
Setting: India
Intervention: high-dose corticosteroids (60 mg/day before tapering)
Comparison: low-dose corticosteroids (30 mg/day before tapering)
Outcomes Anticipated absolute effects* Relative Number Quality of Comments

(95% CI) effect of partici- the evi-
(95% CI) pants dence
(studies) (GRADE)

Informed decisions.

Table 5. High-dose corticosteroids compared to low-dose corticosteroids for treating nerve damage in leprosy (5-
month regimens) (Continued)
Risk with Risk with
low-dose cor- high-dose
ticosteroids corticos-
teroids
Improvement in sensory nerve - - - - - -

function at 1 year - not reported
Improvement in motor nerve func- - - - - - -

tion at 1 year - not reported
Change in nerve pain and in nerve - - - - - -

tenderness at 1 year - not reported
Limitations in activities of daily liv- - - - - - -

ing at 1 year - not reported
Limitations in participation at 1 - - - - - -
year - not reported
Adverse events The trial assessing this compari- Not es- 179 - -
son reported no serious adverse timable (1 RCT)
events from routine clinical ex-
amination during follow-up
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the
relative effect of the intervention (and its 95% CI).

Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the ef-
fect, but there is a possibility that it is substantially different
Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the
effect
Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the
estimate of effect

Table 6. Low-dose corticosteroids compared to short-course corticosteroids for treating nerve damage in leprosy
Low-dose corticosteroids compared to short-course corticosteroids for treating nerve damage in leprosy
Setting: India
Intervention: low-dose corticosteroids (starting at 30 mg/kg/day before tapering to 5 months' completed treatment)
Comparison: short-course corticosteroids (starting at 60 mg/kg/day before tapering to 3 months' completed treatment followed by
2 months' placebo)

Risk with Risk with (studies) (GRADE)
short-course low-dose cor-
ticosteroids

Informed decisions.

Table 6. Low-dose corticosteroids compared to short-course corticosteroids for treating nerve damage in
leprosy (Continued) corticos-
teroids
Improvement in sensory nerve - - - - -

Improvement in motor nerve func- - - - - -

Change in nerve pain and in nerve - - - - -

Limitations in activities of daily liv- - - - - -

Limitations in participation at 1 - - - - -
year - not reported
Adverse events The trial assessing this compari- Not es- 181
CI: confidence interval; RCT: randomised controlled trial

effect
estimate of effect

Table 7. High-dose corticosteroids compared to short-course corticosteroids for treating nerve damage in leprosy
High-dose corticosteroids compared to short-course corticosteroids for treating nerve damage in leprosy
Setting: India
Intervention: high-dose corticosteroids
Comparison: short-course corticosteroids

short-course high-dose
corticos- corticos-
teroids teroids
Improvement in sensory nerve - - - - - -


Informed decisions.

Table 7. High-dose corticosteroids compared to short-course corticosteroids for treating nerve damage in
leprosy (Continued)
Improvement in motor nerve func- - - - - - -
Change in nerve pain and in nerve - - - - - -

Limitations in activities of daily liv- - - - - - -

Limitations in participation at 1 - - - - - -
year - not reported
Adverse events The trial assessing this compari- Not es- 178 - -
CI: confidence interval; RCT: randomised controlled trial

effect
estimate of effect

Table 8. High-dose prednisone compared to low-dose prednisone for treating nerve damage in leprosy
High-dose prednisone compared to low-dose prednisone for treating nerve damage in leprosy
Patient or population: people with nerve damage in leprosy (ulnar neuropathy due to type 1 or type 2 leprosy reaction)
Setting: Brazil
Intervention: high-dose prednisone (starting at 2 mg/kg/day tapering over 6 months)
Comparison: low-dose prednisone (starting at 1 mg/kg/day tapering over 6 months)
Outcomes Anticipated absolute ef- Relative Number Quality of Comments

fects* (95% CI) effect of partici- the evi-
low-dose high-dose
corticos- corticos-
teroids teroids
Improvement in sensory - - - - - Measured by microfil-

nerve function at 1 year - not ament test but sum-
reported marised in a compos-
ite clinical score
Improvement in motor nerve - - - - - Measured by MRC

function at 1 year - not report- scale but summarised
ed

Informed decisions.

Table 8. High-dose prednisone compared to low-dose prednisone for treating nerve damage in leprosy (Continued)
in a composite clinical
score
Change in nerve pain and in - - - - - Measured by visual

nerve tenderness at 1 year - analogue scale but
not reported summarised in a com-
posite clinical score
Limitations in activities of dai- - - - - - -

ly living at 1 year - not reported
Limitations in participation at - - - - - -
1 year - not reported
Adverse events 2 participants reported Not es- 21 (1 RCT) - -

major adverse events, timable
both in the high-dose
group
CI: confidence interval; MRC: Medical Research Council; RCT: randomised controlled trial

effect
estimate of effect

Table 9. Intravenous methylprednisolone and oral prednisolone compared to intravenous normal saline and oral
prednisolone for treating nerve damage in leprosy
Intravenous methylprednisolone and oral prednisolone compared to intravenous normal saline and oral prednisolone for
treating nerve damage in leprosy
Patient or population: people with nerve damage in leprosy type 1 reaction of less than 6 months' duration or with new nerve func-
tion impairment of less than 6 months' duration
Setting: Nepal
Intervention: intravenous methylprednisolone and oral prednisolone
Comparison: intravenous normal saline and oral prednisolone
Outcomes Anticipated absolute effects* (95% Relative Number Quality of Comments

CI) effect of partici- the evi-
Risk with intra- Risk with intra- (studies) (GRADE)
venous normal venous methyl-
saline and oral prednisolone and
prednisolone oral prednisolone
Improvement in nerve There was a downward trend in the - 42 ⊕⊕⊝⊝ The proportion
function total Clinical Severity Scores of both low 1,2 of participants
Assessed with: Clinical groups. There were no statistically sig- (1 RCT) with improve-
Severity Scale nificant differences between the pred- ment in motor
nisolone-alone and prednisolone plus and sensory
Informed decisions.

Table 9. Intravenous methylprednisolone and oral prednisolone compared to intravenous normal saline and oral
prednisolone for treating nerve damage in leprosy (Continued)
methylprednisolone groups at any nerve function
time point was not report-
ed
Change in nerve pain and - - - - - -

in nerve tenderness at 1
year - not reported
Limitations in activities - - - - - -
of daily living at 1 year -
not reported
Limitations in participa- - - - - - -
tion at 1 year - not report-
ed
Adverse events 545 per 1000 551 per 1000 RR 1.01 42 ⊕⊕⊕⊝ 2 people (1
(316 to 955) (95% CI (1 RCT) moderate from each arm
0.58 to 2 of the study) ex-
1.75) perienced at
least 1 adverse
event

effect
estimate of effect
1Outcome measure only narratively described. Significant improvement not defined.

2Small sample size, wide CI (imprecision).

APPENDICES
Appendix 1. Cochrane Neuromuscular Specialised Register (CRS) search strategy

#1 MeSH DESCRIPTOR Leprosy Explode All [REFERENCE] [STANDARD]
#2 hansen*:ti or hansen:ab [REFERENCE] [STANDARD]
#3 lepr*:ti or lepr*:ab [REFERENCE] [STANDARD]
#4 #1 or #2 or #3 [REFERENCE] [STANDARD]
#5 MeSH DESCRIPTOR Adrenal Cortex Hormones Explode All [REFERENCE] [STANDARD]
#6 prednisone* or prednisolone* or cortisone* or cyclosporine* or azathioprine* [REFERENCE] [STANDARD]
#7 methylprednisolone or glucocorticoid* or corticosteroid* or "cortical hormone" or "cortical hormones" [REFERENCE] [STANDARD]
#8 #5 or #6 or #7 [REFERENCE] [STANDARD]
#9 MeSH DESCRIPTOR Peripheral Nervous System Diseases Explode All [REFERENCE] [STANDARD]
#10 neuritis or neuropath* or "nerve damage" or "nerve involvement" [REFERENCE] [STANDARD]
#11 "nerve loss" or "nerve function impairment" or "nerve problem" or "nerve problems" [REFERENCE] [STANDARD]
#12 "sensory loss" or "motor loss" or "motor function loss" [REFERENCE] [STANDARD]
#13 "nerve pain" or "nerve tenderness" [REFERENCE] [STANDARD]

Informed decisions.

#14 reaction* [REFERENCE] [STANDARD]

#15 #9 or #10 or #11 or #12 or #13 or #14 [REFERENCE] [STANDARD]
#16 #4 and #8 and #15 [REFERENCE] [STANDARD]
#17 (#4 and #8 and #15) AND (INREGISTER) [REFERENCE] [STANDARD]
Appendix 2. CENTRAL search strategy

#1 leprosy
#2 MeSH descriptor Leprosy explode all trees
#3 "hansen disease"
#4 (#1 OR #2 OR #3)
#5 "peripheral nervous system diseases" or "peripheral nerves"
#6 MeSH descriptor Peripheral Nervous System Diseases explode all trees
#7 (neuritis or neuralgia or neuropath* or "nerve damage" or "nerve involvement" or "nerve loss" or "nerve function impairment" or
"nerve problem" or "sensory loss" or "motor loss" or "motor function loss" or "nerve pain" or "nerve tenderness" or reaction$)
#8 (#5 OR #6 OR #7)
#9 MeSH descriptor Adrenal Cortex Hormones explode all trees
#10 (prednisolone or prednisone or cortisone or cyclosporin or ciclosporin or azathioprine or methylprednisolone or betamethasone)
#11 (glucocorticoid* or corticosteroid* or prednisolon* or prednison* or cortison* or "cortical hormones" or "cortical hormone" or
cyclosporin* or ciclosporin* or azathioprin* or methylprednisolon* or betamethason*)
#12 (#9 OR #10 OR #11)
#13 (#4 AND #8 AND #12)
Appendix 3. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to June Week 1 2015>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (396862)
2 controlled clinical trial.pt. (89648)
3 randomized.ab. (293733)
4 placebo.ab. (152857)
5 drug therapy.fs. (1782093)
6 randomly.ab. (207091)
7 trial.ab. (303153)
8 groups.ab. (1318490)
9 or/1-8 (3363492)
10 exp animals/ not humans.sh. (4057817)
11 9 not 10 (2863375)
12 exp Leprosy/ (20239)
13 hansen* disease.tw. (829)
14 12 or 13 (20301)
15 exp Adrenal Cortex Hormones/ (344770)
16 Prednisolone/ (29599)
17 Prednisone/ (35381)
18 Cortisone/ (15363)
19 Cyclosporine/ (26754)
20 Azathioprine/ (13448)
21 Methylprednisolone/ (16493)
22 Betamethasone/ (5331)
23 (glucocorticoid$ or corticosteroid$ or prednisolon$ or prednison$ or cortison$ or cortical hormones$ or cyclosporin$ or ciclosporin$
or azathioprin$ or methylprednisolon$ or betamethason$).tw. (216209)
24 or/15-23 (451754)
25 11 and 14 and 24 (385)
26 exp Peripheral Nervous System Diseases/ (119912)
27 (neuritis or neuropath$ or nerve damage or nerve involvement or nerve loss or nerve function impairment or nerve problem or sensory
loss or motor loss or motor function loss or nerve pain or nerve tenderness or reaction$ or reversal reaction$ or type 1 reaction or type
2 reaction).tw. (885639)
28 26 or 27 (969292)
29 11 and 14 and 24 and 28 (260)
30 remove duplicates from 29 (259)

Informed decisions.

Appendix 4. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2015 Week 24>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure/ (43171)
2 double-blind procedure/ (121038)
3 randomized controlled trial/ (373903)
4 single-blind procedure/ (20388)
5 (random$ or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind$) or assign$
or allocat$ or volunteer$).tw. (1464106)
6 clinical trial/ (845836)
7 or/1-6 (2014785)
8 exp animals/ (19964586)
9 exp humans/ (15918733)
10 8 not (8 and 9) (4045853)
11 7 not 10 (1855155)
12 limit 11 to embase (1511872)
13 exp LEPROSY/ (23445)
14 hansen$ disease.tw. (1180)
15 leprosy.tw. (18747)
16 or/13-15 (25694)
17 exp Peripheral Neuropathy/ (53096)
18 neuritis.mp. (16732)
19 neuropath$.mp. (224458)
20 nerve damage.mp. (5418)
21 nerve involvement.mp. (2736)
22 nerve loss.mp. (125)
23 nerve function impairment.mp. (110)
24 nerve problem$.mp. (142)
25 sensory loss.mp. (3119)
26 motor loss.mp. (240)
27 motor function loss.mp. (43)
28 nerve pain.mp. (268)
29 nerve tenderness.mp. (18)
30 reaction$.tw. (1029628)
31 reversal reaction.mp. (604)
32 type 1 reaction$.mp. (225)
33 type 2 reaction$.mp. (135)
34 erythema nodosum leprosum.mp. (1241)
35 or/17-34 (1267303)
36 (steroid$ or glucocorticoid$ or corticosteroid$ or prednisolon$ or prednison$ or cortical hormone$ or cyclosporin A or azathioprin$ or
methylprednisolon$ or betamethason$ or cortison$).mp. (840421)
37 exp decompression surgery/ (36094)
38 (necrolysis or epicondylectomy).mp. (6971)
39 or/36-38 (878190)
40 exp peripheral neuropathy/ (53096)
41 (neuritis or neuropath$ or nerve damage or nerve involvement or nerve loss or nerve function impairment or nerve problem$).mp.
(241878)
42 (sensory loss or motor loss or motor function loss or nerve pain or nerve tenderness or reaction$ or reversal reaction or type 1 reaction
$ or type 2 reaction$ or erythema nodosum leprosum).mp. (1868057)
43 12 and 16 and 39 and 42 (119)
Appendix 5. LILACS (BIREME IAHx) search strategy

(MH:C01.252.410.040.552.386$ or leprosy or lepra or hanseniase) and (prednisone or prednisona or prednisolone or prednisolona or
cortisone or cortisona or cyclosporine or ciclosporina or azathioprine or azatioprina or methylprednisolone or metilprednisolona or
betamethasone or betametasona or glucocorticoid$ or corticosteroid$ or corticoesteroid$) and ((PT:"Randomized Controlled Trial" or
"Randomized Controlled trial" or "Ensayo Clínico Controlado Aleatorio" or "Ensaio Clínico Controlado Aleatório" or PT:"Controlled Clinical
Trial" or "Ensayo Clínico Controlado" or "Ensaio Clínico Controlado" or "Random allocation" or "Distribución Aleatoria" or "Distribuição
Aleatória" or randon$ or Randomized or randomly or "double blind" or "duplo-cego" or "duplo-cego" or "single blind" or "simples-cego"
or "simples cego" or placebo$ or trial or groups) AND NOT (B01.050$ AND NOT (humans or humanos or humanos)))

Informed decisions.

Appendix 6. CINAHL (EBSCOhost) search strategy

Tuesday, June 16, 2015 11:00:19 AM
S34 S15 and S33 7

S33 S16 or S17 or S18 or S19 or S20 or S21 or S22 or S23 or S24 or S25 or S26 or S27 or S28 or S29 or S30 or S31 or S32 752,583
S32 ABAB design* 93
S31 TI random* or AB random* 151,010
S30 ( TI (cross?over or placebo* or control* or factorial or sham? or dummy) ) or ( AB (cross?over or placebo* or control* or factorial or
sham? or dummy) ) 301,434
S29 ( TI (clin* or intervention* or compar* or experiment* or preventive or therapeutic) or AB (clin* or intervention* or compar* or
experiment* or preventive or therapeutic) ) and ( TI (trial*) or AB (trial*) ) 105,987
S28 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) ) 36,870
S27 ( TI (single* or doubl* or tripl* or trebl*) or AB (single* or doubl* or tripl* or trebl*) ) and ( TI (blind* or mask*) or AB (blind* or mask*) )
23,445
S26 PT ("clinical trial" or "systematic review") 127,929
S25 (MH "Factorial Design") 945
S24 (MH "Concurrent Prospective Studies") or (MH "Prospective Studies") 264,883
S23 (MH "Meta Analysis") 22,461
S22 (MH "Solomon Four-Group Design") or (MH "Static Group Comparison") 48
S21 (MH "Quasi-Experimental Studies") 7,381
S20 (MH "Placebos") 9,272
S19 (MH "Double-Blind Studies") or (MH "Triple-Blind Studies") 31,799
S18 (MH "Clinical Trials+") 188,614
S17 (MH "Crossover Design") 13,034
S16 (MH "Random Assignment") or (MH "Random Sample") or (MH "Simple Random Sample") or (MH "Stratified Random Sample") or
(MH "Systematic Random Sample") 69,594
S15 S3 and S14 28
S14 S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 32,265
S13 (cortison*) or (MH "Cortisone") 389
S12 (betamethason*) or (MH "Betamethasone") 540
S11 (methylprednisolon*) or (MH "Methylprednisolone") 2,083
S10 (azathioprin*) or (MH "Azathioprine") 1,245
S9 (cyclosporin A) or (MH "Cyclosporine") 1,689
S8 prednison* 3,674
S7 (prednisolon*) or (MH "Prednisolone") 2,393
S6 corticosteroid* 9,046
S5 (glucocorticoid*) or (MH "Glucocorticoids") 6,518
S4 (steroid) or (MH "Steroids") 11,910
S3 S1 or S2 1,210
S2 hansen disease 11
S1 (leprosy) or (MH "Leprosy") 1,210
FEEDBACK
Comment, 15 June 2016

Summary
“Review question
Are corticosteroids an effective treatment for nerve damage in leprosy?”
Unfortunately, the reviewers appears to have switched from the review question above, to a series of variants, including:
a) Do corticosteroids show a post-treatment effect (several months after the withdrawal of treatment)?
b) Is any post-treatment effect (several months after the withdrawal of treatment) discernible after longstanding nerve damage is treated?
The authors’ conclusions include the following statement:
“…moderate-quality evidence from two RCTs treating either longstanding or mild nerve function impairment did not show corticosteroids
to have a superior effect to placebo on nerve function improvement.”
This statement appears to substitute the question a) above, in place of the Review question. It is an important error.
Informed decisions.

None of the evidence to date refutes the following hypotheses:
A. The sooner nerve damage is detected and treated, the greater the effect of corticosteroids.
B. The biological processes underlying nerve damage can persist after withdrawal of treatment, making it necessary to assess efficacy of
treatment by nerve function improvement during treatment rather than 1 year later.
The review’s quoted failure to find the superiority of corticosteroids over placebo is explicable by the delay (up to 6 months or even
more) until detection and treatment, and by the delay in measuring the efficacy of treatment (delayed for up to 1 year after withdrawal
of treatment).
In short, variables other than the efficacy of corticosteroids sufficiently explain the review’s failure to reject the null hypothesis. Yet the
review question is framed in terms of the efficacy of corticosteroids. This tends to mislead.
Currently, many workers try to protect patients against nerve damage by:
i) Detecting nerve damage as promptly as possible.
ii) Starting corticosteroid treatment as promptly as possible.
iii) Continuing or resuming corticosteroid treatment as required, to contain or reverse nerve damage.
The error described above tends to demotivate workers, skew policy-making in leprosy, and so adversely affect the well-being of patients.
It would be good if such errors were excluded from Cochrane reviews.
The authors deserve appreciation, however, for the robust conclusion that a five-month corticosteroid regimen appears to be more
beneficial than a standard three-month corticosteroid regimen.
Joel Almeida, PhD, MBBS
Declaration of interest: I do not have any affiliation with or involvement in any organisation with a financial interest in the subject matter
of my comment
Reply
The authors of the review thank Dr Almeida for his comments about our Cochrane Systematic Review (CSR) of Corticosteroids for nerve
damage in leprosy. He points out that the data in the review do not exactly reflect the title of the review itself. This is a result of the limited
scope of the trials considered of high enough quality to be included in the review from the predefined selection criteria. There were only
five heterogeneous trials of small size but of low risk of bias that could be included in this CSR. These only provide evidence to support two
variants of the primary question that could be synthesised in the CSR. The evidence from these studies is only of low to moderate quality.
However, in the areas where it is applicable it could be used to influence policy and practice within the limits of the evidence available.
We hope we have made this clear in the review.
There is no high-quality evidence from randomised controlled trials to address the two hypotheses proposed by Dr Almeida, or for that
matter any of the other potential questions that could be asked about the use of corticosteroids for nerve damage in leprosy. We did
not consider a systematic review of the non-randomised literature as this is fraught with heterogeneities and bias that make the data
uninterpretable in any statistically meaningful way. The absence of evidence in these areas is not an indication that corticosteroids do not
work in these areas, and an absence of evidence should not be used to modify clinical policy and practice but to encourage the performance
of appropriately powered, well designed studies which will answer the appropriate questions.
Contributors
Natasja van Veen, on behalf of the review authors; Michael Lunn, Co-ordinating Editor; Brian Dickie, Feedback Editor.
Comment, 30 August 2016

Summary
A randomized controlled trial included by the authors (Van Brakel 2003) compared corticosteroids - prednisolone - given for 4 months,
with placebo. During these 4 months, outcome scores improved significantly more in the prednisolone group. None of the prednisolone
group subjects showed a worsening in monofilament score. In the placebo group, worsening of sensory scores was recorded in 12%. The
difference between groups, in scores at 4 months, attained statistical significance.
Surprisingly, the authors conclude that RCTs “did not show corticosteroids to have a superior effect to placebo on nerve function
improvement.” This conclusion is thoroughly refuted by the evidence cited above.
It is surprising to find such a clearly refuted conclusion in a Cochrane Review.

Informed decisions.

Reply
When this review was conceived and designed, it was felt that using a time period of a year was appropriate for assessment of an outcome in
a disease which is chronic in the tempo of its presentation, has a prolonged duration of treatment, and the aim of that treatment is definitive
‘cure’ of the leprosy. It is recognised that there may be residual end organ damage from the prolonged period of infection, treatment
responses and treatment itself.
We are grateful to Dr Almeida for his comments. We appreciate that in Van Brakel 2003 there was a short-term difference in the
monofilament scores where the prednisolone group did not change and there was a 12% decline in the placebo-treated group which
reached statistical significance. This difference did not persist until 12 months, where there was no difference.
We have not commented on this shorter-term difference for a number of reasons.
1. It did not fit with the prespecified outcome times in the review; this may or may not be correct but the methodology for Cochrane
reviews is very strict and post hoc modifications of the protocol introduce bias which we constantly try to avoid.
2. The difference did not persist and therefore is of questionable relevance. In a definitive treatment with not insignificant potential
adverse effects, an unsustained benefit may not be clinically worthwhile.
3. A 12% change in a monofilament score may be statistically significant but is of questionable clinical significance and probably has no
effect on disability/abilities.
Therefore, from one study there is a short-term and non-sustained difference which is difficult to report as it falls outside the remit of the
review and is of unclear clinical utility.
We have suggested that the initial paragraph of the discussion in the Summary of main results now reads:
“None of the trials found a significant difference in improvement in nerve function between treatment and control groups 12 months after
the start of treatment. We did not explore earlier time points in our prespecified outcome measures. However, one small well performed
study of moderate quality and at low risk of bias reported a small difference in monofilament threshold perception at 4 months in patients
with short term (less than 6 months' duration) disease, which was not sustained to later time points.”
We thank Dr Almeida for his comments and will discuss whether to include a shorter term outcome for future versions of this review. We
hope that there will be some more studies that we will be able to include in a later version to improve the evidence base in this important
disease area.
Contributors
Dr Michael Lunn, Cochrane Neuromuscular Joint Co-ordinating Editor, Natasja van Veen for the review authors, Brian Dickie, Feedback
Editor, Ruth Brassington Managing Editor
Correction by Dr Lunn to feedback above: 21/3/2017
'3. A 12% change in a monofilament score may be statistically significant but is of questionable clinical significance and probably has no
effect on disability/abilities.' should read:
‘3. A decline in 12% of patients on placebo versus 0% treated with prednisolone at 4 months assessed by their monofilament score may
be statistically significant but is of questionable clinical significance and probably has no effect on disability/abilities in the context of the
whole trial, the risks of bias and quality.’
WHAT'S NEW

Date Event Description
21 March 2017 Amended Correction to response to Feedback of 30 August 2017

HISTORY
Protocol first published: Issue 4, 2005
Review first published: Issue 2, 2007

Informed decisions.

Date Event Description
21 November 2016 Feedback has been incorporated Feedback and response incorporated. Edit to the Summary of
main results section of the Discussion.
30 August 2016 Feedback has been incorporated Feedback and response incorporated
14 December 2015 New citation required but conclusions New search fully incorporated.
have not changed
16 June 2015 New search has been performed A search for new trials was undertaken in June 2015. Two new
randomised trial were identified.
4 April 2011 New search has been performed A search for new trials was undertaken in January 2011. No new
randomised trials were identified. 'Risk of bias' tables have been
added.
24 November 2008 New search has been performed A search for new trials was undertaken in January 2008. No new
randomised trials were identified. New relevant non-randomised
information was added to the Discussion.
9 July 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
Liaised with editorial base and co-ordinated contributions from co-authors (NvV)
Drafted protocol (NvV, with input from all)
Ran searches (NvV and Angela Gunn)
Identified relevant titles and abstracts from searches (NvV, JHR)
Obtained copies of trials (NvV)
Selected trials (NvV, JHR)
Extracted data from trials (NvV, JHR)
Entered data into Review Manager (NvV)
Carried out analysis (NvV)
Interpreted data (NvV, with input from all)
Drafted final review (NvV, with input from all)
Updated review (NvV)
DECLARATIONS OF INTEREST
NvV: no conflicts of interest. Her work on this review was supported by a grant from Netherlands Leprosy Relief, which is a charity
(foundation) that supports research in the area of leprosy. The grant was primarily to support PhD study.
PN: I am involved in the Treatment of Early Neuropathy in LEProsy (TENLEP) trials, which include a randomised controlled trial of
alternative steroid regimens in the treatment of leprosy reactions. My role in the TENLEP trials is to provide statistical support. I am also
a member of the International Steering Committee.
WCS: I have not personally benefited financially from any aspect of the review, but I have been a grant holder for a number of related peer-
reviewed research grants administered by my former employer, the University of Aberdeen, including from Lepra for conduct of TRIPOD
trial. I received a fee from the BMJ for a chapter on 'Leprosy in Clinical Evidence'. I received an honorarium from Novartis Foundation for
Sustainable Development for chairing workshops, staff mentoring, and an invited lecture. I have had my travel expenses paid to give invited
lectures and teaching sessions, including the cost of accommodation by various governmental and non-governmental organisations.
JHR: Netherlands Leprosy Relief provided financial support for the PhD study of NvV, of which this review is part. I was NvV's PhD supervisor
at the time and was included in the grant application.

Informed decisions.

SOURCES OF SUPPORT
Internal sources
• No sources of support supplied
External sources
• Netherlands Leprosy Relief, Netherlands.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
'Risk of bias' methodology was updated in accordance with current Cochrane methodology (Higgins 2011). Outcomes for inclusion in
'Summary of findings' tables were listed.
We noted in the previous version of this review that we would revise our outcomes. We have done so, creating a single primary outcome,
improvement in nerve function (sensory and motor), with secondary outcomes of improvement in nerve function at two years, change in
nerve pain at one year, limitations in daily activities at one year, limitations in participation at one year, and adverse events.
INDEX TERMS
Medical Subject Headings (MeSH)

Glucocorticoids [administration & dosage] [adverse effects] [*therapeutic use]; Leprosy [*complications]; Methylprednisolone
[therapeutic use]; Peripheral Nervous System Diseases [diagnosis] [*drug therapy] [etiology]; Prednisolone [administration & dosage]
[therapeutic use]; Randomized Controlled Trials as Topic; Somatosensory Disorders [diagnosis] [*drug therapy] [etiology]
MeSH check words

Humans


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Van Veen NHJ, Nicholls PG, Smith WCS, Richardus JH

Van Veen NHJ, Nicholls PG, Smith WCS, Richardus JH.

Corticosteroids for treating nerve damage in leprosy (Review) i

Corticosteroids for treating nerve damage in leprosy

Editorial group: Cochrane Neuromuscular Group.

Data collection and analysis

Corticosteroids for treating nerve damage in leprosy

Are corticosteroids an effective treatment for nerve damage in leprosy?

Key results and quality of the evidence

The evidence in this review is up to date to June 2015.

Corticosteroids for treating nerve damage in leprosy (Review) 2

Settings: Nepal and Bangladesh

Improvement in motor nerve function at 1 year - - - - - -

Change in nerve pain and in nerve tenderness at 1 - - - - - -

Cochrane Database of Systematic Reviews

Limitations in participation at 1 year - not reported - - - - - -

Adverse events Study population RR 0.83 (0.05 to 75 nerves ⊕⊕⊕⊝ -

GRADE Working Group grades of evidence

1Small sample size.

Patient or population: people with nerve damage (6 to 24 months' duration) in leprosy

Improvement in sensory nerve function at 1 Study population RR 0.97 (0.65 to 71 ⊕⊕⊕⊝ -

Cochrane Database of Systematic Reviews

Change in nerve pain and in nerve tenderness - - - - - -

Adverse events Study population RR 1.87 (0.33 to 92 ⊕⊕⊕⊝ -

GRADE Working Group grades of evidence

1Small sample size.

Cochrane Database of Systematic Reviews

BACKGROUND is to exert a standardised pressure with a ballpoint pen. When

Assessment of nerve function OBJECTIVES

Corticosteroids for treating nerve damage in leprosy (Review) 6

Types of outcome measures We searched the Cochrane Neuromuscular Specialised Register

Corticosteroids for treating nerve damage in leprosy (Review) 7

Assessment of risk of bias in included studies RESULTS

Corticosteroids for treating nerve damage in leprosy (Review) 8

Corticosteroids for treating nerve damage in leprosy (Review) 9

Other potential sources of bias Secondary outcomes

Improvement in sensory nerve function at one year Primary outcomes

Corticosteroids for treating nerve damage in leprosy (Review) 10

Corticosteroids for treating nerve damage in leprosy (Review) 12

Corticosteroids for treating nerve damage in leprosy (Review) 13

Corticosteroids for treating nerve damage in leprosy (Review) 14

Corticosteroids for treating nerve damage in leprosy (Review) 15

patients with acute neuritis. International Journal of Leprosy Job 1989

Croft 1999 Lockwood 2000

Corticosteroids for treating nerve damage in leprosy (Review) 16

Nicholls 2003 Sugumaran 1998

Richardus 2003a Van Veen 2009

Corticosteroids for treating nerve damage in leprosy (Review) 17

References to other published versions of this review Van Veen 2007

Characteristics of included studies [ordered by study ID]

Funding Not reported

Conflicts of interest Not reported

Notes Study conducted in Brazil

Bias Authors' judgement Support for judgement

Blinding of participants Unclear risk Blinding not reported

Blinding of outcome as- Unclear risk Blinding not reported

Incomplete outcome data Low risk No loss to follow-up

Corticosteroids for treating nerve damage in leprosy (Review) 18

Other bias Low risk None identified

Conflicts of interest None of the authors has any competing interest

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Externally controlled computer randomisation

Allocation concealment Low risk Treatments externally assigned

Blinding of outcome as- Low risk Assessors unaware of treatment assignment