Effectiveness of 32 versus 20 weeks of prednisolone in leprosy patients with recent nerve function impairment: A randomized controlled trial.

BACKGROUND: While prednisolone is commonly used to treat recent nerve function impairment (NFI) in leprosy patients, the optimal treatment duration has not yet been established. In this "Treatment of Early Neuropathy in Leprosy" (TENLEP) trial, we evaluated whether a 32-week prednisolone course is more effective than a 20-week course in restoring and improving nerve function. METHODS: In this multi-centre, triple-blind, randomized controlled trial, leprosy patients who had recently developed clinical NFI (<6 months) were allocated to a prednisolone treatment regimen of either 20 weeks or 32 weeks. Prednisolone was started at either 45 or 60 mg/day, depending on the patient's body weight, and was then tapered. Throughout follow up, NFI was assessed by voluntary muscle testing and monofilament testing. The primary outcome was the proportion of patients with improved or restored nerve function at week 78. As secondary outcomes, we analysed improvements between baseline and week 78 on the Reaction Severity Scale, the SALSA Scale and the Participation Scale. Serious Adverse Events and the need for additional prednisolone treatment were monitored and reported. RESULTS: We included 868 patients in the study, 429 in the 20-week arm and 439 in the 32-week arm. At 78 weeks, the proportion of patients with improved or restored nerve function did not differ significantly between the groups: 78.1% in the 20-week arm and 77.5% in the 32-week arm (p = 0.821). Nor were there any differences in secondary outcomes, except for a significant higher proportion of Serious Adverse Events in the longer treatment arm. CONCLUSION: In our study, a 20-week course of prednisolone was as effective as a 32-week course in improving and restoring recent clinical NFI in leprosy patients. Twenty weeks is therefore the preferred initial treatment duration for leprosy neuropathy, after which likely only a minority of patients require further individualized treatment.

Early detection of neuropathy in leprosy: a comparison of five tests for field settings.

BACKGROUND: Early detection and treatment of neuropathy in leprosy is important to prevent disabilities. A recent study showed that the Nerve Conduction Studies (NCS) and Warm Detection Thresholds (WDT) tests can detect leprosy neuropathy the earliest. These two tests are not practical under field conditions, however, because they require climate-controlled rooms and highly trained staff and are expensive. We assessed the usefulness of alternative test methods and their sensitivity and specificity to detect neuropathy at an early stage. METHODS: Through a literature search we identified five alternative devices that appeared user-friendly, more affordable, portable and/or battery-operated: the Neuropad®, Vibratip™, NC-Stat®DPNCheck™, NeuroQuick and the Thermal Sensibility Tester (TST), assessing respectively sweat function, vibration sensation, nerve conduction, cold sensation and warm sensation. In leprosy patients in Bangladesh, the posterior tibial and sural nerves that tested normal for the monofilament test and voluntary muscle test were assessed with the NCS and WDT as reference standard tests. The alternative devices were then tested on 94 nerves with abnormal WDT and/or NCS results and on 94 unaffected nerves. Sensitivity and specificity were the main outcomes. RESULTS: The NeuroQuick and the TST showed very good sensitivity and specificity. On the sural nerve, the NeuroQuick had both a sensitivity and a specificity of 86%. The TST had a sensitivity of 83% and a specificity of 82%. Both the NC-Stat®DPNCheck™ and Vibratip™ had a high specificity (88% and 100%), but a low sensitivity (16% and 0%). On the posterior tibial nerve, the NeuroQuick and the TST also showed good sensitivity, but the sensitivity was lower than for the sural nerve. The Neuropad® had a sensitivity of 56% and a specificity of 61%. CONCLUSIONS: The NeuroQuick and TST are good candidates for further field-testing for reliability and reproducibility. The feasibility of production on a larger scale should be examined.

Normal threshold values for a monofilament sensory test in sural and radial cutaneous nerves in Indian and Nepali volunteers.

The monofilament test (MFT) is a reliable method to assess sensory nerve function in leprosy and other neuropathies. Assessment of the radial cutaneous and sural nerves, in addition to nerves usually tested, can help improve diagnosis and monitoring of nerve function impairment (NFI). To enable the detection of impairments in leprosy patients, it is essential to know the monofilament threshold of these two nerves in normal subjects. The radial cutaneous, sural, ulnar, median and posterior tibial nerves of 245 volunteers were tested. All nerves were tested at three sites on both left and right sides. Normal monofilament thresholds were calculated per test-site and per nerve. We assessed 490 radial cutaneous and 482 sural nerves. The normal monofilament was 2 g (Filament Index Number (FIN) 4.31) for the radial cutaneous and 4 g (FIN 4.56) for the sural nerve, although heavy manual laborers demonstrated a threshold of 10 g (FIN 5.07) for the sural nerve. For median and ulnar nerves, the 200 mg (FIN 3.61) filament was confirmed as normal while the 4 g (FIN 4.56) filament was normal for the posterior tibial. Age and occupation have an effect on the mean touch sensitivity but do not affect the normal threshold for the radial cutaneous and sural nerves. The normal thresholds for the radial cutaneous and sural nerves are determined as the 2 g (FIN 4.31) and the 4 g (FIN 4.56) filaments, respectively. The addition of the radial cutaneous and sural nerve to sensory nerve assessment may improve the diagnosis of patients with impaired sensory nerve function.

Two randomized controlled clinical trials to study the effectiveness of prednisolone treatment in preventing and restoring clinical nerve function loss in leprosy: the TENLEP study protocols.

BACKGROUND: Nerve damage in leprosy often causes disabilities and deformities. Prednisolone is used to treat nerve function impairment (NFI). However, optimal dose and duration of prednisolone treatment has not been established yet. Besides treating existing NFI it would be desirable to prevent NFI. Studies show that before NFI is clinically detectable, nerves often show subclinical damage. Within the 'Treatment of Early Neuropathy in LEProsy' (TENLEP) study two double blind randomized controlled trials (RCT) will be carried out: a trial to establish whether prednisolone treatment of 32 weeks duration is more effective than 20 weeks in restoring nerve function in leprosy patients with clinical NFI (Clinical trial) and a trial to determine whether prednisolone treatment of early sub-clinical NFI can prevent clinical NFI (Subclinical trial). METHODS: Two RCTs with a follow up of 18 months will be conducted in six centers in Asia. In the Clinical trial leprosy patients with recent (< 6 months) clinical NFI, as determined by Monofilament Test and Voluntary Muscle Test, are included. The primary outcomes are the proportion of patients with restored or improved nerve function. In the Subclinical trial leprosy patients with subclinical neuropathy, as determined by Nerve Conduction Studies (NCS) and/or Warm Detection Threshold (WDT), and without any clinical signs of NFI are randomly allocated to a placebo group or treatment group receiving 20 weeks prednisolone. The primary outcome is the proportion of patients developing clinical NFI. Reliability and normative studies are carried out before the start of the trial. DISCUSSION: This study is the first RCT testing a prednisolone regimen with a duration longer than 24 weeks. Also it is the first RCT assessing the effect of prednisolone in the prevention of clinical NFI in patients with established subclinical neuropathy. The TENLEP study will add to the current understanding of neuropathy due to leprosy and provide insight in the effectiveness of prednisolone on the prevention and recovery of NFI in leprosy patients. In this paper we present the research protocols for both Clinical and Subclinical trials and discuss the possible findings and implications. TRIAL REGISTRATION: Netherlands Trial Register: NTR2300 Clinical Trial Registry India: CTRI/2011/09/002022.

Investigation of neuropathic pain in treated leprosy patients in Ethiopia: a cross-sectional study.

Pain can be a significant problem for treated leprosy patients. It can be nociceptive due to tissue inflammation occurring during episodes of immune mediated reactions, or neuropathic due to leprosy affecting the somatosensory system. There are sparse epidemiological data on the prevalence and impact of neuropathic pain in treated leprosy patients. Tools for assessing neuropathic pain have not been validated in leprosy. We have examined nature of pain in a cross-sectional study to determine the prevalence of neuropathic pain (NP) in 80 recently treated leprosy patients in Ethiopia. Pain and depression were evaluated using the General Health Questionnaire (GHQ-12) and the Brief Pain Inventory (BPI) questionnaire. The Douleur Neuropathique en 4 Questions (DN4) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) were used as screening tools for NP. Pain of any type was experienced by 60% of the patients. Pure nociceptive pain was experienced by 43%, pure NP by 11%, and mixed pain by 6%. Of the 14 patients who had NP either alone or in combination with nociceptive pain, 12 had high GHQ-12 scores, indicating possible depression. The DN4 had sensitivity and specificity of 100% and 45%, whereas the LANSS had 85% and 42%, respectively. This is the first study to differentiate nociceptive from NP in leprosy patients. The prevalence of NP is high in recently treated Ethiopian leprosy patients. We have validated the use of DN4 in leprosy and it is easier to use than LANSS. Depression is a common co-morbidity in patients with NP. The high prevalence and morbidity of NP in treated leprosy patients warrant clinical trials to assess the efficacy of pain therapies for leprosy-associated NP.

Inter-rater reliability of WHO 'disability' grading.

The World Health Organization 'disability' grading system was introduced in 1960. It is mainly used as an indicator for early diagnosis or reporting. Disability grades are usually aggregated at national levels. Comparison of data with previous years or comparison of data between programmes may show that patients report earlier for treatment, alternatively, are diagnosed earlier, that is without, or with fewer 'disabilities'. Despite its long and universal use as an epidemiological parameter, the WHO disability grading has not been the subject of reliability studies. In this study, three testers unfamiliar with the grading prior to the study each graded 65 (former) leprosy affected persons. The weighted kappa ranged from 0.87 to 0.89 (95% CI 0.73-1.00) for the highest score and from 0.90 to 0.96 (95% CI 0.90-0.99) for the EHF (Eye, Hand, Foot) score, indicating excellent reliability. The study shows that with limited training and little experience a high degree of reliability in grading 'disabilities' between testers is attainable.