Corticosteroid interventions for treating nerve damage in leprosy
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The objective of this review is to examine systematically the effects of corticosteroid interventions for treating nerve damage in leprosy.
Background
Leprosy is a chronic infectious disease primarily affecting peripheral nerves and skin. The cause of the disease is the bacillus Mycobacterium (M.) leprae, and transmission is most likely to be airborne. Most people (about 90%) who are infected with M. leprae never develop the disease (i.e. symptoms or signs of leprosy) (Meima 2004). One characteristic of M. leprae is its slow generation time resulting in a long incubation period (on average 2 to 5 years) and a slow course of the disease. Further, M. leprae is the only bacillus with a predilection for peripheral nerve tissue. It multiplies best in the cooler parts of the body, such as the skin and superficial nerve trunks (Bryceson 1990). Due to the presence of bacilli in peripheral nerves, nerves may become severely damaged resulting in impairments and disabilities. These consequences do not only have a physical impact on the quality of life of leprosy patients. There is also a psycho‐social component in that they are associated with stigma and fear (Bryceson 1990; Hastings 1985; Meima 2004). Since the introduction of multi drug therapy (MDT), the prevalence of leprosy dropped dramatically as well as the incidence of patients with nerve function impairment (Meima 2004). At the beginning of 2004, about 0.46 million leprosy patients were registered for treatment and during 2003 about 0.5 million new cases were detected globally (WHO 2005). Currently, the WHO estimates the number of people with leprosy‐related impairments at two to three million worldwide (WHO 2004). A prospective study from Bangladesh (BANDS) found that 90 out of 2664 patients in the cohort (3%) had nerve function impairment (NFI) by the time of registration and 175 patients (7%) developed new NFI during five year follow‐up. Of all the patients with NFI (n = 265), 90 individuals (34%) had NFI at registration and 125 patients (47%) developed NFI in the first year after registration when MDT treatment was given. A total of 50 NFI events (19%) occurred in the last three years of follow‐up with none in the last year. Multi‐bacillary (MB) leprosy patients and patients with long‐standing (more than six months) impairment at diagnosis were considered as at high risk for developing new NFI (Croft 2000b; Richardus 2004). In contrast, a prospective cohort study in Ethiopia found a much higher prevalence (324 out of 592 patients, 55%) of impairment at registration probably in part due to long detection delays among these patients (Meima 1999).
Neuritis or inflammation of the nerve due to the presence of bacilli in peripheral nerves is the most important feature of leprosy. There can be neuritis with little or no evidence of nerve damage, but it can also progress to severe loss of nerve function (e.g. muscle paralysis) (Job 1989). The clinical pattern of the disease depends on the response of the host to the bacillary invasion. In tuberculoid leprosy or pauci‐bacillary (PB) patients there is a strong cell‐mediated immune response, but not all bacilli are destroyed, resulting in a few skin lesions and nerves affected. Nerve enlargement and damage are well‐marked and occur in an early stage of the disease. In lepromatous leprosy or MB patients, cell‐mediated immunity is impaired, causing widespread distribution of bacilli throughout the body, including the nerves. Nerve damage develops relatively slowly and is often unnoticed until very late. Borderline leprosy shows a mixture of tuberculoid and lepromatous leprosy. One important feature is immunological instability giving rise to changes in the clinical picture and a tendency to reaction. These reactions are a major cause of rapid nerve damage. Deformities due to nerve damage are worst in borderline leprosy (Bryceson 1990; Job 1989). Reactions are caused by spontaneous fluctuations in the immune response to leprosy bacteria and appear as symptoms and signs of acute inflammation (e.g. swelling and tenderness of skin and nerves). New lesions may also occur (Britton 1998; Bryceson 1990). It is often the reaction symptoms that force people to seek help (Nicholls 2003). The two most common reactions are type 1 reaction or reversal reaction (RR), and type 2 reaction or erythema nodosum leprosum (ENL). Type 1 reactions are caused by an increased immune response leading to inflammation of the skin and nerve trunks. They are most common in borderline leprosy patients, because of their unstable immunological status. Type 2 reaction is a systemic inflammatory response to the deposition of immune complexes and occurs primarily in lepromatous patients (Britton 1998; Bryceson 1990). Both type of reactions are associated with nerve damage and impairment, but RR appears to have a more rapid and severe effect (Bryceson 1990; Hastings 1985). Nerve damage, however, is often not associated with overt signs of leprosy reaction. In fact, it has been observed that up to 68% of patients presenting with nerve function impairment at the time of diagnosis of leprosy had so called 'silent neuritis', that is, loss of nerve function without noticeable signs or symptoms of reaction (Croft 1999).
There are several methods for testing sensory nerve function in leprosy patients. In general, two tests are most commonly used, but disagreement exists about the preferred method for sensory testing (Anderson 1999). First, the Semmes‐Weinstein monofilament test (Bell‐Krotoski 1990) is a sensitive and repeatable method to detect and monitor changes in sensory nerve function impairment by testing touch/pressure sensibility in the hands and feet of patients. The ball‐point pen test is in practice widely used and accepted, because it is simple, cheap and available worldwide (Anderson 1999; Lienhardt 1994; Van Brakel 2003). When used carefully, the prognostic value of ball‐point pen testing is no worse than graded monofilament testing (Van Brakel 2003). One study found that both methods were reliable, the latter test being only slightly better (Anderson 1999). It may be expected that testing with graded monofilaments will give more consistently reliable data because the force or pressure applied by each monofilament is standardised, while even a very light touch with the tip of a ball‐point pen will often exceed easily the human touch sensibility threshold (Anderson 1999; Van Brakel 2003). For measuring muscle strength, there is general consensus about the use of the modified Medical Research Council (MRC) five‐point scale, since it is reported to be reliable (Anderson 1999). There are also simpler 3‐ or 4‐point scales, mainly for field use (Lienhardt 1994).
Corticosteroids (e.g. prednisolone) are generally accepted and available for treating nerve damage and reactions in leprosy (Britton 1998; Croft 2000a; Lockwood 2000; Ustianowski 2003). They act as an anti‐inflammatory agent, by reducing oedema and suppressing the production of pro‐inflammatory enzymes (cytokines) and thereby decreasing compression and scar formation in the nerve (Lockwood 2000; Manandhar 2002). Different studies have examined the effect of corticosteroid treatment for nerve damage in leprosy. The BANDS study also compared patients who were treated with a standard prednisolone regimen of sixteen weeks with patients who were not being given corticosteroids. Results were analysed at four months and twelve months after the start of treatment. There was a higher proportion of nerves with full recovery in the treated group compared to the untreated group. At twelve months, 27 out of 83 treated motor nerves (33%) and 3 out of 36 untreated nerves (8%) had fully recovered. For treated sensory nerves (n = 166), 62 nerves fully recovered (37%) compared with 12 nerves (17%) in the untreated group (n = 69). Of all treated sensory nerves, 22 out of 166 nerves (13%) and 9 out of 83 treated motor nerves (11%) had actually deteriorated. Improvement after twelve months was sustained in 56 out of 83 treated motor nerves (67%) and in 12 out of 36 untreated nerves (3%). Among the treated sensory nerves, 113 out of 166 nerves improved (68%) compared with 43 out of 69 nerves (62%) in the untreated group (Croft 2000a). The duration of the nerve function impairment (NFI) affects the response to treatment. In general, recovery of nerve function loss is likely when the duration of the impairment has been less than six months (Becx‐Bleumink 1990). A randomised controlled trial (RCT) (TRIPOD) comparing corticosteroid therapy with placebo treatment for patients with untreated NFI of more than six months duration, showed that patients in the treatment group did not have a significantly better improvement in NFI than patients in the placebo group (Richardus 2003b). Data from Ethiopia showed that patients with NFI for less than six months and treated with corticosteroids 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 in the long‐term after treatment (Saunderson 2000). Results from other studies show overall improvement levels varying approximately between 60 and 80%. However, comparison of these studies is difficult due to methodological differences between studies (e.g. variation in treatment duration, definition and measurement of outcomes, patient characteristics) (Croft 2000a; Lockwood 2000).
In addition to corticosteroids, there is a search for alternative therapies, because corticosteroids can cause adverse effects, such as peptic ulcer, cataract, or psychosis (Richardus 2003a; Sugumaran 1998). Also, a considerable proportion of patients may not respond to corticosteroid treatment (Lockwood 2000; Marlowe 2004; Sugumaran 1998). Data from the BANDS study showed 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 (Croft 2000a). 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). Some studies have been carried out to examine the added effect of surgical decompression to corticosteroid therapy in improving nerve function (Boucher 1999; Dandapat 1991; Ebenezer 1996; Pannikar 1984). Boucher et al. (Boucher 1999) found that a treatment combining corticosteroids and a surgical intervention (epicondylectomy and surgical decompression) had a significant better result on pain and major but incomplete nerve involvement than corticosteroids alone. However, the studies differed in design and definitions.
Interventions for nerve damage are essential in leprosy control as they can reduce the risk of irreversible impairments and disabilities. The main question now is how effective corticosteroid interventions are in the management of leprosy‐related nerve damage, and compared to other drug‐related or surgical interventions. This review will try to address this question by undertaking a systematic review of these aspects. While this review will focus on evidence from RCTs, it is expected that only a few RCTs have been conducted in this area. Therefore, the results will also be considered in the light of non‐randomised evidence in the Discussion section.
Objectives
The objective of this review is to examine systematically the effects of corticosteroid interventions for treating nerve damage in leprosy.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials and quasi‐randomised controlled trials which compare corticosteroid interventions for treatment of nerve damage in leprosy with other drug‐related or surgical interventions, will be included in this review.
Types of participants
Individuals with clinically diagnosed leprosy, according to Ridley 1966 or WHO 1998 (Table 1), and leprosy‐related nerve damage or severe type 1 leprosy reaction, requiring corticosteroid treatment. Nerve damage or nerve function impairment (NFI) will be defined as clinically detectable impairment of motor or sensory nerve function. It does not include impairment of nerve conduction that is only detectable by electrophysiological means (Croft 1999).
| 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 |
Types of interventions
Any treatment involving: corticosteroids versus placebo or no corticosteroids; corticosteroids versus any other drug‐related or surgical intervention; corticosteroids with any other drug‐related or surgical intervention versus corticosteroids alone or the same intervention without corticosteroids or with placebo.
Types of outcome measures
Primary outcome measures
(1) 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 will consider improvement as determined and defined by the original authors. We will adapt the scores as defined by Van Brakel et al. (Van Brakel 2005) (Table 2). For testing with graded nylon filaments, sensory nerve function impairment will be diagnosed if the monofilament threshold is increased from normal by three or more points for any sensory nerve. Normal thresholds used will be 200 milligrams for the hand and 2 grams for the foot. If the score for any nerve decreased by three or more points from the baseline score, the nerve will be considered as improved. When a non‐graded test is used, such as the ball‐point pen test, a nerve will be diagnosed as impaired if two or more test sites do not feel the stimulus. Improvement for any nerve will be defined as two or more test sites feeling the stimulus, compared to the baseline measurement (Van Brakel 2003).
(2) Improvement in motor nerve function one year 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). When different scales are used, we will transform scores to a 3‐point scale (Table 4). Improvement will be defined as at least one point improvement in score for any muscle compared to the initial score.
Secondary outcome measures
(1) Improvement in nerve function two years after registration.
(2) Change in nerve pain and in nerve tenderness one year after registration, as determined and defined by the original authors. Where possible, we will adapt the scoring systems as defined by Pearson (Pearson 1982) (Table 5).
(3) Occurrence of one or more major adverse events, requiring withdrawal of treatment within one year of registration.
| Colour | Approximate force | Score for hand | Score for foot |
| blue filament felt | 200 mg | 0 | ‐ |
| purple filament felt | 2 g | 1 | 0 |
| red filament felt | 4 g | 2 | 1 |
| orange filament felt | 10 g | 3 | 2 |
| pink filament felt | 300 g | 4 | 3 |
| pink filament not felt | ‐ | 5 | 4 |
| Grade | Definition |
| 5 | Full range of movement of the joint on which the muscle or muscle group is acting. Normal resistance 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. |
| 3‐point scale | 4‐point scale | MRC scale |
| strong | strong | 5 |
| weak | resistance reduced / movement reduced | 4,3 / 2 |
| paralysis | paralysis | 1,0 |
| 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 patients' attention is distracted) |
| 1 | moderate (present if attention is distracted) |
| 0 | severe (very tender and patient withdraws the arm forcibly) |
Search methods for identification of studies
Electronic databases
We will search the Cochrane Neuromuscular Disease Group Register for randomised trials 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 will adapt this strategy to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1966 to the present) and EMBASE (from 1980 to the present). The search strategy for MEDLINE is given in Table 6. Other databases (e.g. LILACS, CINAHL) that may be of relevance will be searched in a similar way.
| Search terms |
| 'mp' denotes keyword search in title, abstract |
Other search strategies
We will check bibliographies of the studies identified, the Current Controlled Trials Register (www.controlled‐trials.com) and contact authors, known experts and organizations in the field to identify additional published or unpublished data. Conference proceedings will be hand searched for additional trials. There will be no language restriction when searching for studies.
Data collection and analysis
Study selection
The titles and abstracts of all the publications identified will be screened to examine whether studies are eligible, according to specified inclusion criteria. Two authors will independently perform this selection. Disagreement will be resolved through discussion in the review team.
Quality assessment
The methodological quality of the included studies will be based on the following criteria: concealment of allocation; blinding of participants and outcome assessors; loss to follow‐up; clear diagnosis; baseline differences and explicit outcome measures mentioned. Each criterion will be assessed as A: adequate, B: unclear or C: inadequate. If one of the criteria is not described in the study, it will be labelled 'inadequate'. Concealment of allocation will be considered adequate if the randomisation process prevents the individual making the allocation from forseeing the treatment assignment. Blinding will be considered adequate if participants and outcome assessors are unaware of the treatment given. Follow‐up will be adequate if the loss to follow‐up is less than 10%. Two authors will independently assess the included studies on methodological quality. If disagreement persists, consensus will be sought by discussion.
Data extraction
Two authors will independently extract data from the included studies onto a data extraction form and a third author will check them. Discrepancies will be resolved by discussion. If there are missing data, the trial authors will be contacted. Authors will not be blinded to trial author, journal or institution.
Analysis
When possible,we will calculate a weighted treatment effect using a fixed effect model across trials with the Cochrane statistical package, Review Manager (RevMan 4.2). Results will be expressed as weighted mean differences (WMD) with 95% confidence intervals (CI) for continuous outcome measures and relative risks (RR) with 95% CI for dichotomous outcomes. Heterogeneity across trials will be assessed using I2. If heterogeneity (I2 > 50%) exists between studies for the primary outcome, reasons for heterogeneity, such as disease severity, dosage and duration of treatment, will be explored. We will repeat the calculations using the random effects model, as this is more conservative and appropriate then a fixed effect model which assumes homogeneous studies. We will analyse separately patients with NFI of less than six months duration and patients with long‐standing impairment (more than six months duration). Studies examining the added effect of a surgical intervention to corticosteroids, will be compared separately from studies comparing corticosteroids alone or with a drug‐related intervention versus another drug‐related intervention or placebo. Sensitivity analyses may also be conducted to examine the effects of excluding poor quality studies. Adverse effects will be expressed as the proportion of patients with serious adverse events.
Discussion
In our discussion, we will consider adverse effects taking non‐randomised literature into account, since randomised studies rarely capture adverse events adequately. We will also consider the costs and cost‐effectiveness of treatment, drawing on non‐randomised evidence when necessary.
| 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 |
| Colour | Approximate force | Score for hand | Score for foot |
| blue filament felt | 200 mg | 0 | ‐ |
| purple filament felt | 2 g | 1 | 0 |
| red filament felt | 4 g | 2 | 1 |
| orange filament felt | 10 g | 3 | 2 |
| pink filament felt | 300 g | 4 | 3 |
| pink filament not felt | ‐ | 5 | 4 |
| Grade | Definition |
| 5 | Full range of movement of the joint on which the muscle or muscle group is acting. Normal resistance 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. |
| 3‐point scale | 4‐point scale | MRC scale |
| strong | strong | 5 |
| weak | resistance reduced / movement reduced | 4,3 / 2 |
| paralysis | paralysis | 1,0 |
| 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 patients' attention is distracted) |
| 1 | moderate (present if attention is distracted) |
| 0 | severe (very tender and patient withdraws the arm forcibly) |
| Search terms |
| 'mp' denotes keyword search in title, abstract |
