Background
Description of the condition
Leprosy is a chronic infectious disease caused by the bacillus Mycobacterium leprae. Leprosy bacilli are probably spread through tiny droplets from the nose or mouth from infected and untreated individuals. When the immune system fails to respond effectively to the antigens of the bacilli, the disease will develop. Often, the first sign of leprosy is a patch on the skin, but damage to peripheral nerves may occur as well. Leprosy can appear in various clinical forms, dependent on the response of the immune system. Some people have only a few skin patches and the number of bacilli is relatively small. This is classified as paucibacillary (PB) leprosy. Other people have many skin patches and a high number of bacilli in their body and are classified as multibacillary (MB) leprosy (ILEP 2001; WHO 2006).
Leprosy infection can be effectively treated with a combination of several antibiotics, multidrug therapy (MDT). Since the introduction of MDT, the number of people affected by leprosy has decreased substantially. At the beginning of 2010, the prevalence was almost 212,000 worldwide. The number of newly detected people was approximately 245,000 during 2009 (WHO 2010 ).
Causes
The body's immune response to the antigens of the leprosy bacilli may cause periods of inflammation in the skin and nerves, so-called reactions. There are two types of reactions: type 1 reaction or reversal reaction (RR) and type 2 reaction or erythema nodosum leprosum (ENL). Reactions can occur before, during and after multidrug therapy and are the main cause of nerve damage and impairment in leprosy (ILEP 2002; WHO 1998; Lockwood 2005). Nerve damage may develop slowly and is often unnoticed until very late. It is often the symptoms of a reaction that force people to seek help (Job 1989; Nicholls 2003).
Impact
Leprosy is most importantly a disabling disease. The World Health Organisation estimates the number of people with disabilities due to leprosy at two to three million worldwide (WHO 2004). People affected by leprosy, especially those with visible deformities and disabilities, fear discrimination and stigmatisation. These people may experience severe social and psychological problems (Heijnders 2004; Leekassa 2004; Rafferty 2005).
Assessment of nerve function
Two tests are commonly used for testing sensory nerve function in people affected by leprosy. These tests work by pressing or touching pre-specified points on the palms and soles with nylon filaments or with the tip of a ball-point pen (Koelewijn 2003; Van Brakel 2003). The Semmes-Weinstein monofilament test (Bell-Krotoski 1990) is a sensitive and repeatable method using standardised monofilaments to detect changes in sensory nerve function. The ball-point pen test is widely used and accepted in practice, because it is simple, cheap and available worldwide (Anderson 1999; Lienhardt 1994; Van Brakel 2003). One difficulty is to exert a standardised pressure with a ball-point pen. The ball-point test can give moderate to good results when it is carefully used by trained staff (Anderson 1999; Koelewijn 2003). Nerve damage can result in loss of muscle strength and function. Muscle strength is usually tested with the modified Medical Research Council (MRC) five-point scale (Brandsma 1981). There are also simpler three-or four-point scales which are mainly used in the field (Lienhardt 1994).
Treatment
Corticosteroids, especially prednisolone, are commonly used for treating severe reactions and nerve damage in leprosy. They work by controlling the acute inflammation and relieving the pain (Britton 1998; Lockwood 2000). The earlier corticosteroids are given after onset of nerve damage, the more likely permanent nerve function impairment will be prevented (Becx-Bleumink 1990; Naafs 1996). The recommended corticosteroid regimen for treating nerve damage starts with 40 mg prednisolone daily and lasts for 12 weeks (WHO 1995). Studies indicate that prolonged prednisolone treatment may be more effective in treating severe reactions and nerve damage (Becx-Bleumink 1990; Little 2001; Naafs 1979; Naafs 2003). Prednisolone seems to be a very effective drug, but it has some shortcomings. Long-term therapy can cause serious adverse effects, such as peptic ulcer, cataract, or psychosis (Richardus 2003a; Sugumaran 1998; WHO 1998). A considerable proportion of people treated for nerve damage do not benefit from corticosteroid treatment (Croft 2000; Lockwood 1993; Saunderson 2000; Schreuder 1998).
Other therapies for improving nerve function and relieving nerve pain, such as surgical decompression of nerves, and azathioprine, have been tested (Boucher 1999; Ebenezer 1996; Marlowe 2004; Pannikar 1984). These interventions are beyond the scope of this review.
Why it is important to do this review
Corticosteroids are the drugs of choice for acute severe reactions and nerve damage, but have drawbacks. The long-term effect of corticosteroids is uncertain and the optimal regimen has not been established. While this review focused on evidence from randomised controlled trials (RCTs), it was expected that only a few RCTs have been conducted in this area. Therefore, the results have also been considered in the light of non-randomised evidence in the Discussion section. This is an update of a review first published in 2007 and previously updated in 2009.
Objectives
To assess the effects of corticosteroids on nerve damage in leprosy.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials and quasi-randomised controlled trials.
Types of participants
Anyone with leprosy confirmed by appropriate clinical signs or symptoms according to Ridley 1966 or WHO 1998 classification ( Table 1) and leprosy-related nerve damage or severe leprosy type 1 reaction, requiring corticosteroid treatment. Nerve damage or nerve function impairment (NFI) was defined as clinically detectable impairment of motor or sensory nerve function. It did not include impairment of nerve conduction that was only detectable by electrophysiological means (Croft 1999).
Types of interventions
Any corticosteroid treatment for nerve damage in leprosy.
The comparators were no treatment or placebo. In the protocol of this review it was stated that we would include corticosteroids plus any other drug-related or surgical intervention versus corticosteroids. Trials which compared corticosteroids plus a complementary therapy versus corticosteroids were excluded, because they did not allow assessment of the value of corticosteroids for treating nerve damage in leprosy which is the subject of this review. Such trials will be considered in future reviews of the relevant intervention for treating nerve damage in leprosy.
Types of outcome measures
Primary outcomes
- Improvement in sensory nerve function one year after registration, as measured with graded nylon filaments or a ball-point pen, and compared to baseline measurement. In general, we considered improvement as determined and defined by the original authors. We adapted the scores as defined by Van Brakel et al. (Van Brakel 2005) ( Table 2). For testing with graded nylon filaments, sensory NFI was diagnosed if the monofilament threshold was increased from normal by three or more points for any sensory nerve. Normal thresholds used were 200 mg for the hand and 2 g for the foot. If the score for any nerve decreased by three or more points from the baseline score, the nerve was considered as improved. When a non-graded test was used, such as the ball-point pen test, a nerve was diagnosed as impaired if two or more test sites did not feel the stimulus. Improvement for any nerve was defined as two or more test sites feeling the stimulus, compared to the baseline measurement (Van Brakel 2003).
- Improvement in motor nerve function one year after registration as determined and defined by the original authors. Improvement in motor nerve function was assessed with the modified MRC grading scale (Brandsma 1981) ( Table 3). Improvement was defined as at least one point improvement in score for any muscle compared to the initial score.
Secondary outcomes
- Improvement in nerve function two years after registration.
- Change in nerve pain and in nerve tenderness one year after registration, as determined and defined by the original authors or according to Pearson's Scale (Pearson 1982) (Table 4).
- Occurrence of one or more major adverse events, requiring withdrawal of treatment within one year of registration.
For the next update we will revise our outcomes, retaining the first primary outcome above as our sole primary outcome and secondary outcomes as follows:
- Improvement in sensory nerve function two years after registration.
- Improvement in motor nerve function one year and two years after registration as determined and defined by the original authors. Improvement in motor nerve function will be assessed with the modified MRC grading scale (Brandsma 1981) ( Table 3). Improvement will be defined as at least one point improvement in score for any muscle compared to the initial score.
- Change in nerve pain and in nerve tenderness one year after registration, as determined and defined by the original authors or according to Pearson's Scale (Pearson 1982) ( Table 4).
- Occurrence of one or more major adverse events, requiring withdrawal of treatment within one year of registration.
- Limitations in daily activities and participation, as measured with leprosy validated instruments (such as Screening of Activity Limitation and Safety Awareness (SALSA) (SALSA 2007), or Participation Scale (Van Brakel 2006)) at one year.
If appropriate we will include a ‘Summary of findings’ table in a future update. The included outcomes will be:
- Improvement in sensory nerve function at one year;
- Improvement in motor nerve function at one year;
- Limitations in activities of daily living (ADL) at one year;
- Limitations in participation at one year;
- Change in nerve pain at one year;
- Adverse events.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Neuromuscular Disease Group Specialized Register (17 January 2011) using the following search terms:
(leprosy or Hansen disease or Hansen's disease) AND (steroid* or corticosteroid* or glucocorticoid* or (cortical hormone*) or prednison* or prednisolon* or cortison* or cyclosporin* or azathioprin* or methylprednisolon* or betamethason* or decompression or neurolysis or epicondylectomy) AND ((exp peripheral nervous system diseases) or (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 (nerve pain) or (nerve tenderness) or reaction* or (reversal reaction) or (erythema nodosum leprosum)).
We adapted this strategy to search the Cochrane Central Register of Controlled Trials (Central) (issue 4, 2010 in The Cochrane Library), MEDLINE (January 1966 to January 2011), EMBASE (January 1980 to January 2011), CINAHL Plus (January 1937 to January 2011) and LILACS (January 1982 to December 2011). The search strategies are given in Appendix 1, Appendix 2, Appendix 3 and Appendix 4.
Searching other resources
We checked bibliographies of the studies identified, the Current Controlled Trials Register (www.controlled-trials.com) and contacted trial authors to identify additional published or unpublished data. Conference proceedings of scientific leprosy meetings were hand searched for additional trials. There was no language restriction when searching for studies.
Data collection and analysis
Selection of studies
Two authors (NvV and JHR) independently screened the titles and abstracts of all the publications identified to examine whether studies were eligible, according to specified inclusion criteria. The review team resolved disagreement through discussion.
Data extraction and management
Two authors (NvV and JHR) independently extracted data from the included studies onto a data extraction form. Discrepancies were resolved by discussion. If there were missing data, the trial authors were contacted. Authors were not blinded to trial author, journal or institution.
Assessment of risk of bias in included studies
The risk of bias in the included studies was based on the following criteria: random sequence allocation, concealment of allocation; blinding of participants and outcome assessors; loss to follow-up (incomplete outcome data), selective reporting and other sources of bias (for example clear diagnosis; baseline differences), as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Each criterion was assessed as high, low or unclear risk. If one of the criteria was not described in the study, it was labelled 'unclear'. Concealment of allocation was considered adequate if the randomisation process prevented the individual making the allocation from foreseeing the treatment assignment. Blinding was considered adequate if participants and outcome assessors were unaware of the treatment given. Follow-up was considered adequate if the loss to follow-up was less than 10%. Two authors (NvV and JHR) independently assessed the included studies for methodological quality. If disagreement persisted, consensus was sought through discussion.
Measures of treatment effect
We used the Cochrane statistical package, Review Manager (RevMan) for statistical data analysis. None of the study results could be pooled meaning that no weighted treatment effect could be calculated. Results were expressed as mean differences (MD) with 95% confidence intervals (CI) for continuous outcome measures and risk ratios (RR) with 95% CI for dichotomous outcomes. We analysed separately participants with NFI of less than six months duration and participants with long-standing impairment (6 to 24 months duration). Adverse effects were expressed as the proportion of participants with major adverse events. It was not possible to perform tests for heterogeneity or sensitivity analysis due to insufficient trials. We will perform such analyses should trials become available in the future.
Adverse effects
In our discussion, we considered adverse effects taking non-randomised literature into account, since randomised studies rarely capture adverse events adequately.
Economic Issues
We considered the costs and cost-effectiveness of treatment, drawing also on non-randomised evidence.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies.
The number of papers found by the new, current search strategies are: MEDLINE 205 (42 new papers), EMBASE 113 (36 new papers), LILACS 8 (6 new papers), CINAHL Plus 7, NMD REGISTER 17 (2 new papers), CENTRAL 12.
We identified ten potentially relevant studies and excluded eight, because they were either not randomised, compared corticosteroids plus a complementary therapy versus corticosteroids, or focused on prevention of nerve damage. One further RCT became available during the original review process. For a description of excluded trials, see table Characteristics of excluded studies.
Three RCTs were included, with the following interventions:
(1) Corticosteroids versus placebo
- Treatment of mild sensory nerve function impairment (less than six months duration) (Van Brakel 2003)
- Treatment of long-standing nerve function impairment (6 to 24 months duration) (Richardus 2003)
(2) High dose corticosteroids versus low dose corticosteroids versus short regimen corticosteroids
- Treatment of severe type 1 reactions (Rao 2006)
For a full description of included trials, see table Characteristics of included studies.
Risk of bias in included studies
For the review authors' 'Risk of bias' assessments for each included study see the table Characteristics of included studies, and Figure 1.
 | Figure 1. Risk of bias summary: review authors' judgements about each risk of bias item for each included study. |
Selection bias
In all three trials (Rao 2006; Richardus 2003; Van Brakel 2003) participants were randomly assigned to either intervention or control group and the allocation concealment was considered adequate.
Performance and detection bias
Participant, personnel and outcome assessor blinding were adequate in the three trials.
Attrition bias
One trial (Richardus 2003) was considered adequate with regard to follow-up and had 3% loss to follow-up. The two other trials had 19% (Rao 2006) and 11% (Van Brakel 2003) loss to follow-up.
Reporting bias
The primary outcome sensory nerve function impairment (NFI) after one year has been measured and reported in two trials (Richardus 2003; Van Brakel 2003). The primary outcome motor NFI after one year has been measured and reported in one trial (Richardus 2003). One trial reported only a clinical outcome, requirement for additional corticosteroids during the 12-month trial period, and no functional outcomes (Rao 2006).
Other bias
Diagnostic criteria
All trials diagnosed and classified leprosy using skin smear or number of skin lesions, according to the internationally accepted diagnostic criteria of the WHO (WHO 1998).
Baseline differences
In all three trials the baseline characteristics in both groups were similar.
Explicit outcomes
The primary outcomes 'improvement in sensory nerve function one year after registration' and 'improvement in motor nerve function one year after registration' were evaluated in two trials (Richardus 2003; Van Brakel 2003) and one trial (Richardus 2003) respectively. Major adverse events were evaluated in two trials (Richardus 2003; Van Brakel 2003). The secondary outcomes 'improvement in nerve function two years after registration' and 'change in nerve pain and in nerve tenderness one year after registration' were not evaluated in any of the trials. One trial evaluated the additional need for corticosteroids during the 12-month trial period in three different corticosteroid regimens (Rao 2006).
Effects of interventions
Corticosteroids versus placebo for participants with mild sensory nerve function impairment (NFI) of less than six months duration (Van Brakel 2003)
Primary outcome measures
(1) Improvement in sensory nerve function one year after registration.
One trial compared prednisolone with placebo in participants with mild sensory NFI (n = 84). One year after the start of treatment results were available for 41 participants in the prednisolone group and 34 participants in the placebo group. Improvement was measured as either a change score between baseline and end of follow-up or as the proportion of participants improved. Change in sensory score between twelve months from the start of treatment and registration was calculated. Sensory testing was done with five coloured graded monofilaments (200 mg, 2 g, 4 g, 10 g, 300 g). For the ulnar nerve, the 200 mg, 2 g, 4 g and 300 g filaments were used. For the posterior tibial nerve the 2 g, 4 g, 10 g, and 300 g filaments were used. Six sites on the palm of the hand and four sites on the sole of the foot were tested. The scoring method is shown in Table 2. Sensory improvement was defined as a reduction by three or more points from baseline to 12 months follow-up. Mean difference between the baseline score and the score at 12 months follow-up were compared for the two treatment groups. After 12 months the mean change was -2.68 ± 2.66 in the prednisolone group and -3.00 ± 2.75 in the placebo group both implying a mean improvement. The improvement was slightly greater in the placebo group but the mean difference 0.32 (95% CI -0.91 to 1.55) between the two groups was not significant (Analysis 01.01.01). The proportion with sensory improvement after one year was also given. In the prednisolone group 33 out of 41 participants (80%) had sensory improvement compared with 27 out of 34 participants (79%) in the placebo group. The difference was not significant (RR 1.01, 95% CI 0.81 to 1.27) (Analysis 01.02.01).
(2) Improvement in motor nerve function one year after registration.
Motor nerve function was not assessed.
Secondary outcome measures
(1) Improvement in nerve function two years after registration.
The trial had a follow-up of one year from the start of treatment.
(2) Change in nerve pain and in nerve tenderness one year after registration.
These outcomes were not measured.
(3) Occurrence of one or more major adverse events, requiring withdrawal of treatment within one year of registration.
Major adverse events were reported in two participants. One person was diagnosed with diabetes, and one with an infected ulcer. The patient with diabetes was taking prednisolone. The patient 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) (Analysis 01.05.01). Also, events requiring full-dose corticosteroids were recorded. These participants were taken out of the trial. In total, 17 participants developed such outcome events. Outcome events were: becoming positive on the ballpen test, developing a type 1 reaction or other events. In the prednisolone group, 11 participants had an outcome event. Outcome events occurred in six control participants. The difference was not statistically significant (RR 0.66, 95% CI 0.27 to 1.59).
Corticosteroids versus placebo for participants with long-standing nerve function impairment (NFI) of 6 to 24 months duration (Richardus 2003)
Primary outcome measures
(1) Improvement in sensory nerve function one year after registration.
One trial compared prednisolone with placebo in participants with long-standing sensory NFI (n = 95). One year after the start of treatment results of sensory nerve function were available for 40 participants in the prednisolone group and 49 participants in the placebo group. Of these 89 participants, 71 had sensory NFI only and 18 had had both sensory and motor NFI at randomisation. Improvement was measured as either a change score between baseline and end of follow-up or the presence of improvement. Changes in sensory score between 12 months from the start of treatment and registration were calculated. Sensory testing was done following the same procedure as Van Brakel et al. (Van Brakel 2003). Sensory improvement was defined as a reduction by three or more points from baseline to 12 months follow-up. Mean differences between the baseline score and the score at 12 months were compared for the two treatment groups. After 12 months the mean difference was -1.25 ± 1.66 in the prednisolone group and -1.67 ± 3.02 in the placebo group indicating a mean improvement in both. The improvement was slightly greater in the placebo group but the mean difference 0.42 (95% CI -0.57 to 1.41) between the two groups was not significant (Analysis 01.01.02). The proportion with sensory improvement after one year was also given for participants with only sensory impairment (n = 71). In the prednisolone group 17 out of 30 participants (57%) had sensory improvement compared with 24 out of 41 participants (59%) in the placebo group. The difference was not significant (RR 0.97, 95% CI 0.65 to 1.45) (Analysis 01.02.02).
(2) Improvement in motor nerve function one year after registration.
One trial compared prednisolone with placebo treatment in participants with long-standing motor NFI (n = 21). One year after the start of treatment results of motor nerve function were available for 11 participants in the prednisolone group and 10 participants in the placebo group. Of these 21 participants, 3 had motor NFI only and 18 had both sensory and motor NFI. Improvement was measured as either a change score between baseline and end of follow up or as the proportion of participants improved. Motor nerve function of the ulnar nerve was assessed with the modified MRC grading scale. The MRC scale was inverted for the purposes of this trial. A score of two or more points was considered as severe motor NFI. Change in motor score between 12 months from the start of treatment and registration was calculated. A negative change score was considered an improvement. After 12 months the mean difference was -0.18 ± 0.98 in the prednisolone group and -0.30 ± 1.06 in the placebo group, both indicating a mean improvement. The improvement was slightly greater in the placebo group but the mean difference 0.12 (95% CI -0.76 to 1.00) between the two groups was not significant (Analysis 01.03). The presence of motor improvement after one year was also given for participants with pure motor impairment (n = 3). In the prednisolone group one out of one patient had motor improvement compared with zero out of two participants in the placebo group but the difference was not significant (RR 4.50, 95% CI 0.32 to 63.94).
Secondary outcome measures
(1) Improvement in nerve function two years after registration.
The trial had a follow-up of one year from the start of treatment.
(2) Change in nerve pain and in nerve tenderness one year after registration.
These outcomes were not measured.
(3) Occurrence of one or more major adverse events, requiring withdrawal of treatment within one year of registration.
Five participants came out of the trial due to symptoms of possible major adverse events. Three of them were in the prednisolone group (diabetes, infected ulcer, 'hypersensitivity' to the tablets), and the other two were assigned to placebo treatment (diabetes, peptic ulcer). The difference between the two groups was not significant (RR 1.87, 95% CI 0.33 to 10.64) (Analysis 01.05.02). Another 30 participants, 15 participants in both groups, developed events which required full-dose corticosteroid treatment (type 1 or type 2 reactions, any signs of recent NFI). These were taken out of the trial.
High dose corticosteroids versus low dose corticosteroids versus short regimen corticosteroids for participants with severe type 1 reactions (Rao 2006).
None of the outcome measures as prespecified for this review were evaluated in this trial. The primary endpoint was the requirement for additional corticosteroids during the 12-month trial period. A poor outcome was defined as a failure to respond to treatment in terms of changes to skin lesions, nerve pain or tenderness, or nerve function, or recurrences of skin or nerve lesions and needing extra corticosteroids. At the end of the 12-month period, 41 out of 90 participants (46%) in the short course group (2940 mg over three months) needed extra corticosteroids. In the group of participants receiving a low dose of prednisolone (2310 mg over five months) this was 28 out of 91 (31%), and 21 out of 88 participants (24%) following a high dose prednisolone regimen (3500 mg over five months) required additional prednisolone. The difference between the high dose and low dose five-month regimen was not significant (RR 0.78, 95% CI 0.48 to 1.26) (Analysis 02.01). The RR of needing additional corticosteroids was significantly less with the high dose five-month course than with the three-month course (RR 0.52, 95% CI 0.34 to 0.81) (Analysis 03.01). The RR of needing additional corticosteroids was just significantly less with the low dose five-month course than with the three-month course (RR 0.68, 95% CI 0.46 to 0.99) (Analysis 04.01). No major adverse events were reported during the follow-up period.
Discussion
Summary of main results
Corticosteroids are the cornerstone of management in acute nerve damage in leprosy, but the long-term effect of corticosteroids remains uncertain.
Overall completeness and applicability and quality of the evidence
Three randomised controlled trials were available for this review. The interventions and outcomes were too heterogeneous to be entered in a meta-analysis. The numbers of participants included in the trials were small and did not allow for subgroup analysis. The variability between studies and the limitations in sample size made it difficult to draw any robust conclusions.
None of the trials found a significant difference in improved nerve function between treatment and control group 12 months after start of treatment. One of the two trials comparing corticosteroids with placebo treated participants with long-standing NFI, who are less likely to benefit from corticosteroids than those with acute NFI (Richardus 2003). The other placebo-controlled trial treated participants with mild sensory impairment and hypothesised that corticosteroid treatment might prevent 'monofilament sensory loss' progressing to 'ballpen sensory loss' (Van Brakel 2003). Detection of NFI in the field however is still primarily done with ballpen rather than monofilaments. The question, whether corticosteroids are beneficial in treating acute NFI or type 1 leprosy reaction in a field setting in the longer term compared to placebo, remains unclear. The study comparing three different corticosteroid regimens reported that participants following a short duration course were more likely to have a poor outcome in terms of needing extra corticosteroids. The main objective of this trial was to investigate failure to respond to the given corticosteroid regimen. Unfortunately, the effect of different corticosteroid regimens on nerve function improvement was not evaluated, which makes this trial unsuitable for comparison with the other included trials.
The occurrence of adverse effects was not significantly higher in the corticosteroid group compared to the placebo group (RR 1.47, 95% CI 0.35 to 6.24) (Analysis 05.01). While only two trials, which were limited in size and power, reported adverse effects, this evidence was inconclusive. One meta-analysis, including 6602 patients, reviewed the adverse effects of corticosteroid treatment compared to placebo treatment in randomised, double-blind, controlled trials. The review found that minor dermatologic adverse effects (for example moon face, acne), diabetes, hypertension and psychosis were significantly more often reported in patients receiving steroids compared to patients in the placebo group. The occurrence of peptic ulcer did not differ significantly between both groups and should not be considered a contra-indication for corticosteroid treatment (Conn 1994). One study reported on the occurrence of adverse events in the three TRIPOD trials. The study found that the relative risk of acne, fungal infections and gastric pain was increased in the corticosteroid group. Most of these events were reversible and did not require discontinuation of treatment or removal from the trials. No increased risk of major adverse events, such as hypertension, diabetes, cataract and psychosis, was found in the corticosteroid group compared to the placebo group. With strict procedures and good surveillance, standardised corticosteroid therapy can be safely administered (Conn 1994; Richardus 2003; Richardus 2003a).
None of the trials included quality of life measures or cost-effectiveness calculations when these could be useful indicators of the effectiveness of interventions. Little has been reported about the impact of treating nerve damage in leprosy in terms of quality of life and costs. One randomised controlled study compared ambulatory care and hospitalisation in the management of neuritis due to leprosy reactions. Outcome measures were estimated costs per patient and improvement in quality of life score (QOL). The study found that the mean total costs for an ambulatory patient were significantly lower than for a hospitalised patient. The QOL score after treatment was higher than the pre-treatment score in both groups, but the difference was not significant. However, the study sample was very small (n = 26) and larger trials may shed more light upon economic and well-being aspects of neuritis management in leprosy (Ravi 2004). A review article addressing the socioeconomics of leprosy control estimates the costs of several aspects of leprosy management. Costs of corticosteroid treatment are, for instance, lower when applied under field conditions and when volunteers are involved (Naik 1998).
Potential biases in the review process
The search process was elaborate and to our knowledge no other randomised controlled trials were available for this review.
Agreements and disagreements with other studies or reviews
Several non-randomised studies have examined the effect of corticosteroids for treating severe reactions and nerve damage in leprosy. The response to corticosteroid treatment seems to depend on the severity and duration of NFI before the start of treatment. One study found that 35% of patients having complete anaesthesia and 67% with moderate sensory impairment improved to good function three months after the start of corticosteroid treatment. For patients with complete motor paralysis or moderate motor impairment, respectively 11% and 55% of the patients recovered to good function (Van Brakel 1996). The RCT of treating mild sensory impairment found that a significant higher proportion 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, at least much longer than the duration of a standard steroid course (Saunderson 2000). Recovery of nerve function loss is more likely when the duration of NFI has been less than six months (Becx-Bleumink 1990; Britton 1998). To illustrate, data from Ethiopia showed that patients with NFI for less than six months and treated with steroids had full recovery in 50 out of 57 nerves (88%), while in patients with recurrent or chronic NFI only 20 out of 39 nerves (51%) had fully recovered after up to ten years after treatment (Saunderson 2000). This is in line with the RCT of treating long-standing NFI which found that 19 out of 41 nerves (46%) treated with prednisolone improved (Richardus 2003). However, even in the placebo group, 25 out of 51 nerves (49%) showed spontaneous improvement after 12 months. Other studies also reported spontaneous nerve function improvement in untreated individuals (Croft 2000; Saunderson 2000; Schreuder 1998).
The optimal corticosteroid regimen has not been established. Recommendations about the optimal dose and duration of steroid therapy have changed over time (Naafs 2003; Pearson 1981). The principles of a steroid therapy are that it should start with a dose that is sufficient to control the inflammation rapidly. Then the dose should be tapered off until the reaction has settled. The ideal would be a steroid course adjusted and tailored to the individual's situation, but this may be only possible in referral centres (Rose 1991). Currently, a standard 12-week course of prednisolone is recommended by the WHO which can be safely used in the field (WHO 1995). Other studies have suggested that a prolonged regimen might be more beneficial (Little 2001; Naafs 1979; Naafs 2003; Rose 1991). One small retrospective study compared a short-term steroid treatment (two months) with a prolonged steroid treatment (3 to 18 months) for type 1 reaction in borderline leprosy patients. It was found that the latter treatment gave better results on improving motor nerve function than the shorter treatment and did not increase the risk of adverse events. The critical dose to control a reaction after the initial period was considered to be 15 to 20 mg daily (Naafs 1979). One study examined the effects of prednisolone treatment on the cellularity and cytokine profiles of leprosy skin type 1 reactions. The results showed that prednisolone treatment decreased cytokine levels significantly only after 28 days from the start of treatment. Some patients continued to have cytokine production for one to six months. This study illustrates the slow response to steroid therapy and continuing activity for several months (Little 2001). While these non-randomised studies already suggested the benefits of a prolonged steroid course, the RCT comparing three corticosteroid regimens confirms this in reporting that a longer duration of prednisolone treatment gave less poor outcomes than a short course of prednisolone (Rao 2006). Another randomised controlled trial assessed two different oral steroid treatment regimens for ulnar neuropathy in type 1 and type 2 leprosy reactions (n = 21) (Garbino 2007). Patients with type 1 (n = 12) reaction or type 2 reaction (n = 9) were randomly allocated to either a steroid regimen starting with 2 mg/kg/day (experimental group, n = 12) or a steroid regimen starting with 1 mg/kg/day (control group, n = 9). Both regimens were gradually tapered off during the six-month trial period if possible. Nerve pain (visual analogue scale), nerve palpation (grade 0-5), sensory nerve function (monofilaments) and motor nerve function (MRC scale) were measured and summarised in a clinical score. In addition, a neurophysiological evaluation (for example nerve conduction) was done. Results were reported at the end of the six-month trial period, comparing experimental and control group (type 1 and type 2 reactions) and type 1 versus type 2 reactions. All ulnar nerves showed improved clinical scores at the end of six months, but no significant differences were found, either between experimental and control group or type 1 and type 2 reactions. Improvement in neurophysiological parameters was significant during the first month of treatment in the experimental group, but this benefit had disappeared at the end of six months. The author concludes that nerve responses to steroids were dose-dependent in both types of reactions during the first month of treatment with the initial higher doses of steroids giving better results. Nerves that were affected for less than three months showed a similar response when treated with either the high dose or low dose steroid regimen, implying that a low dose steroid therapy might be adequate for very recent nerve damage.
According to other authorities, a substantial proportion of individuals treated for nerve damage do not respond to corticosteroids. The overall nerve function improvement levels vary approximately between 60% and 80% after steroid therapy (Croft 2000). Croft 2000 reported that 27 out of 83 treated nerves with motor impairment (33%) and 53 out of 166 treated nerves with sensory impairment (32%) did not improve or had deteriorated twelve months after the start of treatment. In a study in Thailand, 27 out of 77 patients who were treated with prednisolone (35%) showed no improvement or a worsening of NFI (Schreuder 1998).
One randomised controlled trial examined the effect of prophylactic use of steroids in 636 newly diagnosed multibacillary patients (Smith 2004). This study showed that a low dose prophylactic steroid regimen reduced the risk of NFI at the end of four months (RR 3.9, 95% CI 2.1 to 7.3), but the effect was not sustained at one year (RR 1.3, 95% CI 0.9 to 1.8). Repeat use of steroid prophylaxis for a longer period than four months may sustain the benefit, but this needs to be further examined. A non-randomised follow-up study evaluated the effect of the combined use of steroids and MDT in preventing nerve damage in patients with pure neural (PN) leprosy (n = 24) (Jardim 2007). Patients with PN leprosy present with nerve damage or enlarged peripheral nerves but without having any sign of skin manifestation or skin patches. Patients received a paucibacillary MDT regimen for six months plus a daily morning dose of 1 mg/kg of prednisolone for one month followed by a progressive 10 mg monthly reduction over the remaining five months. Assessment of sensory nerve function, motor nerve function and nerve pain was done with monofilaments, MRC scale and visual analogue scale respectively, at diagnosis and 12 months after the start of MDT. One out of 20 (5%) patients with initial sensory NFI had improved and 5 out of 21 (24%) patients with initial motor NFI showed improvement 12 months after the start of MDT. In four out of nine patients (44%), relief of neural pain was reported. Nerve conduction parameters were also measured and a significant reduction of nerve conduction block was found. The authors indicate the need for a double-blind, placebo-controlled study for further evaluation of steroids as prophylactic drugs.
An alternative therapeutic approach for treating nerve damage in leprosy has been surgical decompression of acutely inflamed nerves. This approach has been the subject of another Cochrane review (Van Veen 2009).
There is an ongoing search for new therapies, because steroids are not always effective, may cause serious adverse effects and because their long-term effect is unclear. One recent quasi-randomised controlled trial compared an eight-week course of prednisolone combined with azathioprine with a 12-week course of prednisolone alone for treating severe type 1 reactions (Marlowe 2004). The trial did not find a significant difference in clinical severity scores between the two treatment groups, but the study was limited in size (n = 40). Therapies which are used for other immune-mediated conditions, such as ciclosporin or combinations of immunosuppressants may be promising. It is plausible that these therapies may be effective for treating nerve damage in leprosy, but evidence from RCTs is lacking (Lockwood 2000).
A non-randomised follow-up study assessed the effects of ciclosporin treatment in 33 Ethiopian and 10 Nepali leprosy patients with severe type 1 reactions (Marlowe 2007). Patients received an initial dose ciclosporin of 5 mg/kg/day together with 40 mg oral prednisolone for the first five days. Thereafter patients only received ciclosporin for 12 weeks. This study used the clinical severity score as defined by Marlowe et al. (Marlowe 2004). The study found that among patients with acute NFI, 5 out of 16 (31%) had improved sensory scores and 9 out of 18 (50%) had improved voluntary muscle testing (VMT) scores whilst on treatment. One patient maintained the sensory NFI and five patients maintained motor NFI at 12 weeks after stopping ciclosporin. In patients with chronic NFI, 13 out of 21 (62%) had improved sensory scores and 10 out of 20 (50%) had improved voluntary muscle testing scores. Six patients maintained the sensory nerve function improvement and four patients maintained motor nerve function improvement at 12 weeks after stopping ciclosporin. Nerve pain and tenderness scores improved in 21 out of 41 (51%) patients. The study reported jaundice (n = 1), raised serum creatinine levels (n = 2), loss of appetite (n = 1), indigestion, dizziness and epigastric pain (n = 1) and hypertension (n = 3) as side effects of ciclosporin treatment. The authors suggest that ciclosporin monotherapy may be an effective treatment for severe type 1 reactions with few adverse effects.
Authors' conclusions
Implications for practice Evidence from the three randomised controlled trials is insufficient to draw robust conclusions about the effect of corticosteroids for treating nerve damage in leprosy. Two trials, of which one treated long-standing nerve function impairment and the other mild sensory impairment, did not show significantly better outcomes with corticosteroids than placebo for treating nerve damage in leprosy in the long term. However in a third trial, a five-month corticosteroid regimen was significantly more beneficial than a three-month corticosteroid regimen. Standard corticosteroid regimens are not significantly more harmful than placebo treatment, despite known adverse effects of corticosteroids. |
Implications for research There is a need for high quality randomised controlled trials to establish the value and optimal dose of corticosteroid regimens and to examine the efficacy and safety of new therapies. Future trials should pay more attention to non-clinical aspects, such as costs and impact on quality of life, because these are highly relevant indicators for both policy makers and participants. |
Acknowledgements
We would like to thank Dr AM Anderson and Dr JA Garbino for providing additional information and the Cochrane Neuromuscular Disease Group for advice and help.
The Cochrane Neuromuscular Disease Group editorial base is supported by the MRC Centre for Neuromuscular Diseases.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Index terms
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Appendices
Appendix 1. MEDLINE (OvidSP) search strategy
1 randomized controlled trial.pt.
2 controlled clinical trial.pt.
3 randomized.ab.
4 placebo.ab.
5 drug therapy.fs.
6 randomly.ab.
7 trial.ab.
8 groups.ab.
9 or/1-8
10 exp animals/ not humans.sh.
11 9 not 10
12 exp Leprosy/
13 hansen* disease.tw.
14 12 or 13
15 exp Adrenal Cortex Hormones/
16 Prednisolone/
17 Prednisone/
18 Cortisone/
19 Cyclosporine/
20 Azathioprine/
21 Methylprednisolone/
22 Betamethasone/
23 (glucocorticoid$ or cortisteroid$ or prednisolon$ or prednison$ or cortison$ or cortical hormones$ or cyclosporin$ or ciclosporin$ or azathioprin$ or methylprednisolon$ or betamethason$).tw.
24 or/15-23
25 11 and 14 and 24
26 exp Peripheral Nervous System Diseases/
27 (neuritis or neuropath$ 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.
28 11 and 14 and 24 and (26 or 27)
Appendix 2. EMBASE (OvidSP) search strategy
1 crossover-procedure/
2 double-blind procedure/
3 randomized controlled trial/
4 single-blind procedure/
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$).tw.
6 clinical trial/
7 or/1-6
8 exp animals/
9 exp humans/
10 8 not (8 and 9)
11 7 not 10
12 limit 11 to embase
13 exp LEPROSY/
14 hansen$ disease.tw.
15 leprosy.tw.
16 or/13-15
17 exp Peripheral Neuropathy/
18 neuritis.mp.
19 neuropath$.mp.
20 nerve damage.mp.
21 nerve involvement.mp.
22 nerve loss.mp.
23 nerve function impairment.mp.
24 nerve problem$.mp.
25 sensory loss.mp.
26 motor loss.mp.
27 motor function loss.mp.
28 nerve pain.mp.
29 nerve tenderness.mp.
30 reaction$.tw.
31 reversal reaction.mp.
32 type 1 reaction$.mp.
33 type 2 reaction$.mp.
34 erythema nodosum leprosum.mp.
35 or/17-34
36 (steroid$ or glucocorticoid$ or corticosteroid$ or prednisolon$ or prednison$ or cortical hormone$ or cyclosporin A or azathioprin$ or methylprednisolon$ or betamethason$ or cortison$).mp.
37 exp decompression surgery/
38 (necrolysis or epicondylectomy).mp.
39 or/36-38
40 exp peripheral neuropathy/
41 (neuritis or neuropath$ or nerve damage or nerve involvement or nerve loss or nerve function impairment or nerve problem$).mp.
42 (sensory loss or motor loss or motor function loss or nerve pain or nerve tenderness or reaction$ or reversal reaction or type 1 reaction$ or type 2 reaction$ or erythema nodosum leprosum).mp.
43 12 and 16 and 39 and 42
Appendix 3. LILACS ( BIREME/PAHO/WHO) search strategy
(Mh leprosy OR Tw hansen$ disease OR Tw leprosy) and
((Tw steroid$ OR Tw glucocorticoid$ OR Tw corticosteroid$ OR Tw prednisolon$ OR Tw prednison$ OR Tw cortical hormone$ OR Tw cyclosporin A OR Tw azathioprin$ or Tw methylprednisolon$ OR Tw betamethason$ OR Tw cortison$) OR (Mh Decompression Surgery OR Tw decompression OR Tw neurolysis OR Tw epicondylectomy)) [Words] and
(Mh Peripheral Neuropathy OR Tw neuritis OR Tw neuropath$ OR Tw nerve damage OR Tw nerve involvement OR Tw nerve loss Tw nerve function impairment OR Tw nerve problem OR Tw sensory loss OR Tw motor loss OR Tw motor function loss OR Tw nerve pain OR Tw nerve tenderness OR Tw reaction$ OR Tw reversal reaction OR Tw type 1 reaction$ OR Tw type 2 reaction$ OR Tw erythema nodosum leprosum) [Words] and
((Pt randomized controlled trial OR Pt controlled clinical trial OR Mh randomized controlled trials OR Mh random allocation OR Mh double-blind method OR Mh single-blind method) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Pt clinical trial OR Ex E05.318.760.535$ OR (Tw clin$ AND (Tw trial$ OR Tw ensa$ OR Tw estud$ OR Tw experim$ OR Tw investiga$)) OR ((Tw singl$ OR Tw simple$ OR Tw doubl$ OR Tw doble$ OR Tw duplo$ OR Tw trebl$ OR Tw trip$) AND (Tw blind$ OR Tw cego$ OR Tw ciego$ OR Tw mask$ OR Tw mascar$)) OR Mh placebos OR Tw placebo$ OR (Tw random$ OR Tw randon$ OR Tw casual$ OR Tw acaso$ OR Tw azar OR Tw aleator$) OR Mh research design) AND NOT (Ct animal AND NOT (Ct human and Ct animal)) OR (Ct comparative study OR Ex E05.337$ OR Mh follow-up studies OR Mh prospective studies OR Tw control$ OR Tw prospectiv$ OR Tw volunt$ OR Tw volunteer$) AND NOT (Ct animal AND NOT (Ct human and Ct animal))) [Words]
Appendix 4. CINAHL (EBSCOhost) search strategy
S34 S15 and S33
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
S32 ABAB design*
S31 TI random* or AB random*
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) )
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*) )
S28 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) )
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*) )
S26 PT ("clinical trial" or "systematic review")
S25 (MH "Factorial Design")
S24 (MH "Concurrent Prospective Studies") or (MH "Prospective Studies")
S23 (MH "Meta Analysis")
S22 (MH "Solomon Four-Group Design") or (MH "Static Group Comparison")
S21 (MH "Quasi-Experimental Studies")
S20 (MH "Placebos")
S19 (MH "Double-Blind Studies") or (MH "Triple-Blind Studies")
S18 (MH "Clinical Trials+")
S17 (MH "Crossover Design")
S16 (MH "Random Assignment") or (MH "Random Sample") or (MH "Simple Random Sample") or (MH "Stratified Random Sample") or (MH "Systematic Random Sample")
S15 S3 and S14
S14 S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13
S13 (cortison*) or (MH "Cortisone")
S12 (betamethason*) or (MH "Betamethasone")
S11 (methylprednisolon*) or (MH "Methylprednisolone")
S10 (azathioprin*) or (MH "Azathioprine")
S9 (cyclosporin A) or (MH "Cyclosporine")
S8 prednison*
S7 (prednisolon*) or (MH "Prednisolone")
S6 corticosteroid*
S5 (glucocorticoid*) or (MH "Glucocorticoids")
S4 (steroid) or (MH "Steroids")
S3 S1 or S2
S2 hansen disease
S1 (leprosy) or (MH "Leprosy")
Appendix 5. CENTRAL search strategy
#1leprosy
#2MeSH descriptor Leprosy explode all trees
#3"hansen disease"
#4(#1 OR #2 OR #3)
#5"peripheral nervous system diseases" or "peripheral nerves"
#6MeSH 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)
#9MeSH 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 cortisteroid* 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)
What's new
Last assessed as up-to-date: 16 January 2011.
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History
Protocol first published: Issue 4, 2005
Review first published: Issue 2, 2007
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Contributions of authors
Liaised with editorial base and co-ordinated contributions from co-reviewers (NVV)
Drafted protocol (NVV, with input from all)
Ran searches (NVV)
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
PN, JHR and WCS were involved in a series of randomised controlled trials on prevention of impairment and disability in leprosy (TRIPOD trials) examining the effect of corticosteroids in the prevention and treatment of nerve function impairment in leprosy.
PN: My role in the TENLEP trials is to provide statistical support. I am also a member of the International Steering Committee. Recruitment to the study has not yet begun. The results will not be available for publication until 2014.
JHR: Netherlands Leprosy Relief provided financial support for the study of which this review is part.
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 employer, the University of Aberdeen.
NVV: none known.
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 updated in accordance with current Cochrane methodology (Higgins 2011). Outcomes for inclusion in any future 'Summary of findings' tables listed.
Index terms
Medical Subject Headings (MeSH)
Glucocorticoids [*therapeutic use]; Leprosy [*complications]; Peripheral Nervous System Diseases [diagnosis; *drug therapy; etiology]; Prednisolone [therapeutic use]; Randomized Controlled Trials as Topic; Somatosensory Disorders [diagnosis; *drug therapy; etiology]
MeSH check words
Humans