Intervenciones para las úlceras y otras alteraciones cutáneas causadas por el daño nervioso de la lepra
Resumen
Antecedentes
A finales de 2016; 145 países informaron a la Organización Mundial de la Salud (OMS) de más de 173 000 casos nuevos de lepra en todo el mundo. En los últimos 20 años, más de 16 millones de personas han recibido tratamiento contra la lepra en todo el mundo. Las principales complicaciones de la afección son las lesiones y ulceraciones causadas por la pérdida de sensibilidad debido al daño nervioso. En esta revisión se exploraron las intervenciones para prevenir o tratar el daño secundario a la piel en pacientes afectados por lepra (enfermedad de Hansen). Esta es una actualización de una revisión Cochrane publicada en 2008.
Objetivos
Evaluar los efectos de la educación, la información, los programas de autocuidado, los apósitos, el cuidado de la piel, el calzado y otras medidas para prevenir y curar el daño secundario a la piel en pacientes afectados por lepra.
Métodos de búsqueda
Se actualizaron las búsquedas en las siguientes bases de datos hasta julio de 2018: Registro Especializado del Grupo Cochrane de Piel (Cochrane Skin Group), CENTRAL, MEDLINE, Embase, AMED, LILACS y CINAHL. También se realizaron búsquedas en cinco registros de ensayos, tres bases de datos de la literatura gris y en las listas de referencias de los estudios incluidos para obtener referencias adicionales a ensayos controlados aleatorios (ECA) pertinentes.
Criterios de selección
ECA o ensayos controlados cuasialeatorios o ensayos aleatorios cruzados (cross‐over) que incluyeran a cualquier persona con lepra y daño potencial a los nervios periféricos que hubiese sido tratada con cualquier intervención diseñada para prevenir el daño, cicatrizar las úlceras existentes y prevenir el desarrollo de nuevas úlceras. Las comparaciones elegibles fueron la atención habitual, ninguna intervención u otras intervenciones (p.ej. otros tipos de apósitos o calzado).
Obtención y análisis de los datos
Se cumplió con los procedimientos metodológicos estándar previstos por Cochrane. Las medidas de resultado primarias fueron la prevención de las úlceras, la cicatrización de las úlceras existentes y los eventos adversos. Se utilizó GRADE para evaluar la calidad de la evidencia de cada resultado.
Resultados principales
Se incluyeron 14 ensayos (854 participantes). Once estudios informaron sobre el sexo (hombres: 472, mujeres: 157). La edad de los participantes varió de 18 a 74 años. La mayoría de los participantes tenían una única herida, principalmente no infectada, en un pie, que había estado presente durante menos de un año. Solo siete estudios informaron la duración total del estudio (no hubo seguimiento posterior al tratamiento), que fue de un promedio de seis meses (rango: 1 a 12 meses). Los estudios se realizaron en Brasil, Etiopía, Egipto, Indonesia, México, Corea del Sur e India. Muchas evaluaciones del 'Riesgo de sesgo' fueron calificadas como de riesgo poco claro debido a la información limitada. Seis estudios tuvieron un alto riesgo de sesgo en al menos un dominio, incluido el sesgo de selección y de deserción.
Trece estudios evaluaron diferentes intervenciones para el tratamiento de las úlceras existentes, uno de ellos también evaluó la prevención de nuevas úlceras. Un estudio tuvo como objetivo prevenir las alteraciones cutáneas, como el agrietamiento y las fisuras. Las intervenciones investigadas incluyeron: terapia con láser, diodo emisor de luz (LED), cinta de zinc, pentoxifilina intralesional, campos magnéticos pulsados, cera terapéutica, ketanserina, gel de membrana amniótica humana, fenitoína, zapatos de yeso y calzado.
No existe seguridad en cuanto a los siguientes resultados clave, debido a que la certeza de la evidencia es muy baja. Todos los puntos temporales se midieron a partir del inicio.
Tres estudios compararon cinta de zinc versus otras intervenciones e informaron resultados a favor de la cinta de zinc. Un estudio comparó la cinta de zinc versus sulfato de magnesio: al mes, el número de úlceras cicatrizadas y la reducción del área media de la úlcera fueron mayores con la cinta de zinc (cociente de riesgos [CR] 2,00; intervalo de confianza [IC] del 95%: 0,43 a 9,21; y diferencia de medias [DM] ‐14,30 mm²; IC del 95%: ‐26,51 a ‐2,09; respectivamente, 28 participantes). Otro estudio comparó cinta de zinc y povidona yodada y encontró que aunque hubo una mayor reducción del área de la úlcera después de seis semanas de tratamiento con cinta de zinc, no hubo una diferencia clara debido al amplio IC del 95% (DM 128,00 mm²; IC del 95%: ‐110,01 a 366,01; 38 participantes). El tercer estudio (90 participantes) comparó cinta adhesiva de zinc con gasa impregnada con Eusol, y encontró que el tiempo de cicatrización de las úlceras profundas fue menor en comparación con la cinta de zinc: 17 días (IC del 95%: 12 a 20) versus 30 días (IC del 95%: 21 a 63). Los eventos adversos solo se recogieron en el estudio que comparó cinta de zinc con gasa impregnada con Eusol: no hubo signos de sensibilización cutánea en ninguno de los dos grupos a los dos meses.
Dos estudios compararon fenitoína tópica versus apósito de solución salina e informaron resultados a favor de la fenitoína. Un estudio informó una mayor reducción porcentual media del área de la úlcera después de cuatro semanas con fenitoína al 2% (DM 39,30%; IC del 95%: 25,82 a 52,78; 23 participantes), y el otro estudio informó una mayor reducción porcentual media del volumen de la úlcera (16,60%) después de cuatro semanas con fenitoína (IC del 95%: 8,46 a 24,74; 100 participantes). No se observaron eventos adversos con ninguno de los tratamientos durante el período de tratamiento de cuatro meses (dos estudios, 123 participantes). La prevención de las úlceras no se evaluó en estos estudios ni en los estudios del cinc, debido a que las intervenciones no se realizaron para un uso preventivo.
Dos estudios compararon el calzado de protección (con o sin autocuidado) con 1) botas de cloruro de polivinilo (PVC) o 2) campos magnéticos pulsados más autocuidado y calzado de protección. En el estudio que comparó zapatos de lona versus botas de PVC, ninguno de los 72 participantes con cicatrices al inicio del estudio desarrolló nuevas úlceras durante un año de seguimiento. Se evaluó la cicatrización de las úlceras en 38 participantes de este estudio, aunque no está claro si hay alguna diferencia entre los grupos. En el estudio que comparó los campos magnéticos pulsados (además del autocuidado y el calzado de protección) con el autocuidado y el calzado solo en 33 participantes, no se conoce si el volumen medio de úlceras a las cuatro o cinco semanas de seguimiento fue diferente entre los grupos; este estudio no evaluó la prevención de las úlceras. Solo se presentó información sobre los eventos adversos en el estudio que comparó los zapatos de lona con las botas de PVC; los autores afirmaron que las botas de PVC podrían calentarse al ser expuestas a la luz solar intensa y posiblemente quemar los pies.
Conclusiones de los autores
Sobre la base de la evidencia disponible, no fue posible establecer conclusiones sólidas acerca de los efectos de las intervenciones incluidas. Las principales limitaciones de la evidencia fueron el riesgo de sesgo alto o incierto que incluyó sesgo de selección, de realización, de detección y de deserción; la imprecisión debido a la escasez de participantes en los estudios; y la falta de direccionalidad a partir de la medición deficiente de los resultados y las intervenciones no aplicables. Las investigaciones futuras deben informar con claridad los resultados importantes, como los eventos adversos, y evaluar las intervenciones ampliamente disponibles, que deben incluir tratamientos dirigidos a la prevención. Estos ensayos deben garantizar la ocultación de la asignación, el cegamiento y un tamaño de la muestra adecuado.
PICO
Resumen en términos sencillos
Tratamientos para úlceras (heridas) y otras alteraciones cutáneas en personas con lepra
Pregunta de la revisión
Se revisó la evidencia acerca de los efectos de los tratamientos (p.ej. educación, autocuidado, apósitos, cuidado de la piel o calzado) diseñados para prevenir o tratar el daño cutáneo en personas con lepra e individuos con daño potencial a los nervios periféricos. Los tratamientos podían ser comparados con la atención habitual, ningún tratamiento u otro tratamiento. La evidencia está actualizada hasta julio 2018.
Antecedentes
La lepra (enfermedad de Hansen) es una enfermedad infecciosa de larga duración a nivel global, que puede provocar complicaciones como lesiones y desarrollo de heridas (úlceras), en especial en los pies. El daño a los nervios y músculos a largo plazo afecta la calidad de vida del paciente, lo cual da lugar a dificultades mentales y económicas. El diagnóstico tardío es la causa principal de discapacidad, por lo que la clave para un tratamiento efectivo es el diagnóstico y tratamiento tempranos, y el reconocimiento y tratamiento tempranos del daño nervioso, combinados con educación sanitaria efectiva para prevenir el daño en las extremidades. Esta revisión procuró considerar la incertidumbre con respecto a la mejor manera de prevenir y tratar el daño cutáneo.
Características de los estudios
Se incluyeron 14 ensayos (854 participantes con lepra). La mayoría de los participantes solo tenía una herida en un pie. Las heridas eran principalmente simples (no infectadas), variaban en tamaño y profundidad, y tenían menos de un año de antigüedad; algunas heridas presentaban más complicaciones. La edad de los participantes osciló entre 18 y 74 años de edad. En los 11 estudios que informaron del género, se incluyeron más hombres. Se realizaron estudios en Brasil, Etiopía, Egipto, Indonesia, México, Corea del Sur y la India, principalmente en clínicas ambulatorias. La mayoría de los estudios no informaron las fuentes de financiamiento.
Los tratamientos se compararon principalmente con apósitos secos o apósitos impregnados con diferentes soluciones. Otras comparaciones incluyeron yeso especial, zapatos de lona y remojo de los pies.
Resultados clave
Los tratamientos evaluados incluyeron: terapia con láser, diodo emisor de luz (LED, por sus siglas en inglés), cinta o pasta de zinc, inyecciones de pentoxifilina, exposición a campos magnéticos pulsados, cera terapéutica, gel de ketanserina, gel de membrana amniótica, polvo de fenitoína, zapatos de yeso y calzado. Los resultados se midieron desde el inicio del tratamiento. Los siguientes resultados clave se basan en evidencia de muy baja certeza, por lo que no existe seguridad en cuanto a estos resultados.
Tres estudios compararon la cinta de zinc con otras intervenciones: glicerina de sulfato de magnesio, povidona yodada o gasa impregnada con Eusol. Después de un mes de tratamiento, el número de úlceras cicatrizadas fue mayor y el área de la úlcera fue menor en el grupo de cinta de zinc en comparación con la glicerina de sulfato de magnesio. No hubo diferencias claras en la reducción del área de la úlcera a las seis semanas al comparar la cinta de zinc con la povidona yodada. El tiempo de cicatrización de las úlceras profundas en el grupo de cinta de zinc fue de 17 días en comparación con 30 días con gasa impregnada con Eusol. Este estudio tampoco informó signos de sensibilización cutánea en ninguno de los grupos a los dos meses; los otros dos estudios no proporcionaron datos sobre los eventos adversos.
Dos estudios compararon fenitoína tópica con apósito de agua salada. Un estudio mostró una mayor reducción en el área de la úlcera con fenitoína. El otro estudio encontró una mayor reducción en el volumen de la úlcera a favor de la fenitoína. Ambos estudios midieron este resultado después de cuatro semanas de tratamiento. No se informaron eventos adversos en ninguno de los estudios.
Los cinco estudios recién descritos no evaluaron la prevención de las úlceras, debido a que las terapias se realizaron para el tratamiento en lugar de para la prevención.
Dos estudios compararon el calzado de protección (con o sin autocuidado) con botas de cloruro de polivinilo (PVC, por sus siglas en inglés ‐ una forma de plástico) o campos magnéticos pulsados más autocuidado y calzado de protección. En el estudio que comparó los zapatos de lona con las botas de PVC, ninguno de los participantes que tenían cicatrices al principio desarrolló nuevas úlceras durante un año. No hubo una diferencia clara entre los grupos en el número de pacientes cuyas úlceras habían cicatrizado. En el estudio que evaluó los campos magnéticos pulsados, no se midió la prevención de nuevas úlceras; sin embargo, no hubo una diferencia clara entre los grupos en cuanto al volumen de las úlceras cuatro o cinco semanas después del inicio del tratamiento. Solo un estudio presentó información sobre los eventos adversos: las botas de PVC podrían calentarse mucho al ser expuestas a la luz solar intensa, con la posibilidad de quemarse.
Certeza de la evidencia
La evidencia se consideró de muy baja certeza, lo que significa que los resultados son ambiguos. Hubo inquietudes con respecto a cómo se asignaron los participantes a los tratamientos, si los participantes y los investigadores del estudio sabían qué tratamiento se había recibido y el número de participantes que abandonaron los estudios.
Authors' conclusions
Summary of findings
| Zinc tape compared to magnesium sulphate glycerin for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with magnesium sulphate/glycerin | Risk with Zinc tape | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (number of ulcers healed after 1 month) | Study population | RR 2.00 | 28 | ⊕⊝⊝⊝ | ‐ | |
| 143 per 1000 | 286 per 1000 | |||||
| Primary outcome: healing of ulcers (mean ulcer area (mm3) | The mean ulcer area was 56.7 | MD 14.3 lower | ‐ | 28 | ⊕⊝⊝⊝ | ‐ |
| Priimary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: costs | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (such as 35% lost to follow‐up, consecutive cases were randomly allocated, no blinding of outcome assessor, and potential unit of analysis error). Also downgraded two levels for imprecision due to sparse data and wide confidence intervals. | ||||||
| Zinc tape compared to povidone iodine (10%) for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with povidone iodine (10%) | Risk with zinc tape | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (mean reduction of ulcer area at 6 weeks (mm2)) | The mean reduction of ulcer area at six weeks was 260 | MD 128 higher | ‐ | 38 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: costs | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (quasi‐randomised trial, high loss to follow‐up, and no reporting of blinding of outcome assessor), and two levels due to imprecision (1 study, few participants, wide confidence interval). | ||||||
| Adhesive zinc tape compared to gauze soaked in eusol for ulceration caused by nerve damage in leprosy | |||||
| Patient or population: ulceration caused by nerve damage in leprosy | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
| Risk with gauze soaked in eusol | Risk with adhesive zinc tape | ||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (days) | Total number of participants was 90 and they had a total of 128 plantar ulcersb. The average healing time was shorter for the group treated with zinc tape. The results varied between the two hospitals involved. In one hospital, it took about 20 days (CI 18 to 23) for superficial ulcers to heal in the zinc tape group versus about 30 (CI 27 to 33) in the gauze group. For deep ulcers the average healing time was two weeks more. In the other hospital, the average number of days to heal in the zinc tape group for superficial wounds was about 13 (CI 9 to 15) days and 23 (CI 16 to 28) days in the gauze group. For deep ulcers it took 17 days (CI 12 to 20) in the zinc tape group and 30 (CI 21 to 63) in the gauze group. | ‐ | 90 | ⊕⊝⊝⊝ | |
| Primary outcome: adverse events (skin sensitisation at 2 months) | The study authors reported: "No signs of skin sensitization were observed in either the tape‐treated or the gauze‐treated wounds". | ‐ | 90 (1 RCT) | ⊕⊝⊝⊝ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | Not clear how or if this was adequately measured. However, the study authors say: "The zinc tape has the following advantages: 1. shorter healing time, 2. low cost, 3. easy application, 4. more convenient for patients: (a) can be worn under shoes without causing pressure; (b) socially more acceptable, no bandages are needed". | ‐ | 90 (1 RCT) | ⊕⊝⊝⊝ | |
| Secondary outcome: costs | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | |||||
| GRADE Working Group grades of evidence | |||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (allocation random alternate basis, no blinding outcome assessor, and inadequate reporting of data), and two levels for imprecision (few participants)). | |||||
| Topical ketanserin (2%) compared to clioquinol cream (3%) or zinc paste for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with clioquinol cream (3%) or zinc paste | Risk with topical ketanserin (2%) | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (healing of ulcer at 3 months) | Study population | RR 6.00 | 66 | ⊕⊝⊝⊝ | ‐ | |
| 61 per 1000 | 364 per 1000 | |||||
| Primary outcome: adverse events | Treatment was not suspended in any of the patients because of side effects | ‐ | 66 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (randomisation procedure not reported, blinding not reported, and unclear if appropriate statistical analysis used) and two levels due to imprecision (1 study, very wide confidence interval). | ||||||
| Topical phenytoin compared to saline dressing for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with saline dressing | Risk with topical phenytoin (2%) | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (mean percentage of ulcer volume reduction at 4 weeks (Bansal 1993)) | The mean percentage reduction of ulcer volume was 55.5% | MD 16.60% higher | ‐ | 100 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcers (mean percentage reduction of ulcer size area at 4 weeks (Bhatia 2004)) | The mean percentage reduction of ulcer size area was 49.1% | MD 39.30% higher | 23 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Primary outcome: adverse events (up to 4 weeks) | No adverse effects were observed in any of the patients treated with phenytoin or normal saline. | ‐ | 123 (2 RCTs) | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (non‐adequate random sequence generation, unit of analysis error) and two levels due to imprecision (sparse data and consequently wide confidence interval). | ||||||
| Footwear ‐ canvas shoes compared to PVC boots for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with PVC boots | Risk with canvas shoes | |||||
| Primary outcome: prevention of ulcer (number of persons developing new ulcers at 1 year) | None of the 45 participants with scars developed new ulcers | None of the 27 participants with scars developed new ulcers | ‐ | 72 (1 RCT) | ⊕⊝⊝⊝ | Seventy‐two participants had scars (not ulcers) at the start of the study (27 in canvas group, 45 in PVC group) and none of these developed new ulcers during the year. |
| Primary outcome: healing of ulcer (number of persons being ulcer‐free at 1 year) | Study population | RR 1.16 | 38 | ⊕⊝⊝⊝ | ‐ | |
| 692 per 1000 | 803 per 1000 | |||||
| Primary outcome: healing of ulcer (number of persons having ulcers not healed at 1 year) | Study population | RR 0.52 | 38 | ⊕⊝⊝⊝ | ‐ | |
| 308 per 1000 | 160 per 1000 | |||||
| Primary outcome: adverse events | One adverse comment was that PVC boots could become very hot in strong sunlight, with possibility of burning the feet | ‐ | 38 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | The canvas shoes were socially acceptable, but 85% of farmers rated them as good for their work, rather than "excellent" (8%) at first follow‐up at three months. More than 80% rated the PVC boots as excellent for social acceptability and work suitability. | ‐ | 110d (1 RCT) | ⊕⊕⊕⊝ | ‐ | |
| Secondary outcome: costs | See comment | ‐ | 110d (1 RCT) | ‐ | Costs not reported. Study authors only reported that canvas shoes and PVC boots cost the same. PVC boots are more durable than canvas shoes. | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (unclear randomisation, unclear blinding) and two levels due to imprecision (1 study, small number of participants, wide confidence interval). | ||||||
| Padded moulded double‐rocker plaster shoe compared to padded below‐knee plaster for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with padded below‐knee plaster | Risk with padded moulded double‐rocker plaster shoe | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (ulcers fully or nearly healed at 6 weeks) | Study population | RR 0.96 | 55 | ⊕⊝⊝⊝ | ‐ | |
| 875 per 1000 | 840 per 1000 | |||||
| Primary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | Study authors stated: "The MD shoe is more acceptable to the patient" | ‐ | 55 | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: costs of intervention | Study authors stated: "The MD shoe is ......cheaper to apply and, more important.." | ‐ | 55 | ⊕⊝⊝⊝ | ‐ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded by four levels to very low‐certainty evidence. Two levels due to study limitations (no information on baseline characteristics; unit of analysis is ulcers, not patients; unclear randomisation procedure; unclear if blinding of outcome assessor), one level due to indirectness (padded moulded double‐rocker plaster shoe and padded below‐knee plasters might not be acceptable interventions today for people with leprosy), and one level due to imprecision (1 study, small number of participants). | ||||||
| Exposure to pulsed magnetic fields (in addition to self‐care and protective footwear) compared to self‐care and footwear for ulceration and other skin changes caused by nerve damage in leprosy | |||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
| Risk with self‐care and footwear | Risk with exposure to pulsed magnetic fields (in addition to self‐care and protective footwear) | ||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (at 4 to 5 weeks) | In the control group, the geometric mean volumes of the ulcers were 2843 cu mm and 1478 cu mm on the day of admission and at the end of treatment (P = 0.03); the corresponding values in the PMF group were 2428 cu mm and 337 cu mm, respectively (P < 0.001). A decrease in the volume of 40% or more was observed in 53% of control patients and 89% of PMF participants (P = 0.02): a decrease of 80% or more was observed in none of the controls and in 33% of PMF participants. | ‐ | 33 (1 RCT) | ⊕⊝⊝⊝ | |
| Primary outcome 2 (healing of ulcer): Mean volume of ulcers at four to five weeks | The mean volume (cm2) after four to five weeks was 1.48 | MD was 1.14 lower (5.37 lower to 3.09 higher) | ‐ | 33 (1 RCT) | ⊕⊝⊝⊝ |
| Primary outcome 3 (adverse events) | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome 1 (quality of life) | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome 2 (acceptability of treatment) | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome 3 (cost of intervention) | The authors state: "The cost of construction of an enclosure is around Rs. 5000/‐ (about 150 USD) and the function generator together with the centre‐zero milliammeter costs another Rs. 6000/‐ (about 180 USD). Where uninterrupted power supply is a problem, an inverter and a 12‐volt battery together costing about RS. 5000/‐ (about 150 USD) would be required." | ‐ | 33 (1 RCT) | ⊕⊝⊝⊝ | |
| *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). | |||||
| GRADE Working Group grades of evidence | |||||
| a Downgraded by three levels. One level due to study limitations (unclear randomisation procedure, 7 of 20 patients lost to follow‐up) and two levels due to imprecision (1 study with few participants). | |||||
| Low‐level laser therapy compared to simple dressing for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with simple dressing | Risk with low‐level laser therapy | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (size of ulcer (area) at 12 weeks (cm2)) | The mean size of ulcer (area) after 12 weeks was 4.4 | MD 0.60 lower | ‐ | 23 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcer (size of ulcer (depth) at 12 weeks (mm)) | The mean size of ulcer (depth) after 12 weeks was 5.4 | MD 1.30 mm lower | ‐ | 23 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse effects | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: costs | Costs not analysed between groups, but trial authors state: "Patients have an average of 3.4 simple dressings per week at the dressing service of UREMC, resulting in an estimated expenditure of USD 100,000 per year on disposable dressing material alone." | ‐ | 23 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels. One level due to study limitations (unclear allocation concealment, no blinding of outcome assessor), one level due to indirectness (we are unsure if the intervention ‐ laser therapy ‐ is available to people with ulcers caused by nerve damage in leprosy) and two levels due to imprecision (1 study, small sample size, wide confidence interval). | ||||||
| Intralesional pentoxifylline compared to daily simple dressing for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with daily simple dressing | Risk with intralesional pentoxifylline | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (complete healing of ulcer at 4 weeks) | Study population | OR 9.00 | 40 | ⊕⊝⊝⊝ | ‐ | |
| 100 per 1000 | 500 per 1000 | |||||
| Primary outcome: healing of ulcer (ulcer depth (cm) at 4 weeks) | The mean ulcer depth was 0.45 | MD 0.22 cm lower | ‐ | 40 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events (at 4 weeks) | The patients were asked about any possible side effects such as pain, skin rash, discolouration, or discomfort. There were no side effects, except tolerable pain during the injection in intervention group. | ‐ | 40 | ⊕⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment and unclear if there was blinding of outcome assessor) and two levels due to imprecision (1 small study, very wide confidence intervals). | ||||||
| Light‐emitting diode (LED) irradiation compared to conventional dressing therapy for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with conventional dressing therapy | Risk with LED irradiation | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (mean change of wound size (mm3) after 8 months treatment) | The mean change of wound size was 26.55 | MD 311.47 higher | ‐ | 60 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (concealment or sequence generation not reported, no blinding) and two levels due to imprecision (only 1 study, few participants, wide confidence interval). | ||||||
| Wax therapy compared to foot soaks for skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with foot soaks | Risk with wax therapy | |||||
| Primary outcome: healing of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Tertiary outcome: prevention and treatment of other skin changes (number of feet being fissure‐ and callous‐free at 6 weeks) | Study population | RR 2.22 | 44 | ⊕⊝⊝⊝ | ‐ | |
| 300 per 1000 | 666 per 1000 | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: adverse effects | ‐ | ‐ | ‐ | ‐ | Not reported | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | Not reported | |
| Secondary outcome: acceptability of treatment (at 6 weeks) | "Patients given wax therapy felt subjectively much better than those who had foot soaks" | ‐ | 44 | ⊕⊝⊝⊝ | ‐ | |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded, and study authors are not clear in numbers of persons or feet reported), two levels due to imprecision (1 study with 44 participants, wide confidence interval) and one level due to indirectness (wax therapy probably not available to most people with leprosy; treatment is given in hospital). | ||||||
| hAMMSC‐CM + vitamin C compared to hAMMSC‐CM for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with hAMMSC‐CM | Risk with hAMMSC‐CM + vitamin C | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Primary outcome: healing of ulcer (size, cm², at 8 weeks) | The mean reduction was 1.70 | MD 0.31 cm2 higher (0.35 lower to 0.97 higher) | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Primary outcome: healing of ulcer (depth, cm², at 8 weeks) | The mean reduction was 0.35 | MD 0.10 cm2 lower (0.17 lower to 0.03 lower) | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Primary outcome: adverse events | "No adverse events were encountered in any group" | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | ||
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | Not reported | |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded), two levels due to imprecision (1 study with a total of 66 patients with three arms). | ||||||
| hAMMSC‐CM + vitamin E compared to hAMMSC‐CM for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with hAMMSC‐CM | Risk with hAMMSC‐CM + vitamin E | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Primary outcome: healing of ulcer (size, cm2 at 8 weeks) | The mean reduction was 1.70 | MD 1.14 cm2 higher (0.35 higher to 0.97 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcer (depth, cm2 at 8 weeks) | The mean reduction was 0.35 | MD 0.08 cm2 lower (0.17 lower to 0.01 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | Study authors reported: "No adverse events were encountered in any group" | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | ||
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded), two levels due to imprecision (1 study with a total of 66 patients with 3 arms). | ||||||
| hAMMSC‐ CM +vitamin E compared to hAMMSC‐CM + vitamin C for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with hAMMSC‐CM + vitamin C | Risk with hAMMSC‐CM + vitamin E | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Primary outcome: healing of ulcer (size, cm2, at 8 weeks) | The mean reduction was 2.01 | MD 0.83 cm2 higher (0.03 lower to 1.69 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcer (depth, cm2, at 8 weeks) | The mean reduction was 0.25 | MD 0.02 cm2 higher (0.06 lower to 0.10 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | Study authors reported: "No adverse events were encountered in any group" | 44 (1 RCT) | ⊕⊝⊝⊝ Very lowb | ‐ | ||
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded), two levels due to imprecision (1 study with a total of 66 patients with three arms). | ||||||
Background
We have included a glossary with an explanation of some of the terms used, see Table 1.
| Term | Definition |
| Afferent nerves | Sensory nerves that carry information from the outside world, such as sensations of heat, cold, and pain, to the brain and spinal cord. |
| Autonomic fibres | Nerve fibres that collectively make up the sympathetic (involuntary) and parasympathetic ('relaxation response') parts of the autonomic peripheral nervous system. Common symptoms of autonomic nerve damage include an inability to sweat normally and change in vasodilatation. |
| Bacilli | Plural of bacillus, bacteria. |
| Capillary haemodynamics | Blood flow in the capillaries, where oxygen transfer occurs in the body. |
| Efferent nerves | Motor nerves that transmit impulses from the brain and spinal cord to the muscles. |
| Facial nerve | It is composed of motor, sensory fibres and autonomic fibres. The important motor part innervates the facial muscles responsible for eye closure and mouth and facial movements. In leprosy, the eye is at risk of corneal ulceration for exposure and decreased lachrymal gland function. |
| Fibroblast | A large flat cell that secretes the proteins that form collagen and elastic fibres and the substance between the cells of connective tissue. |
| Medial nerve | It is composed of motor, sensory, and autonomic fibres. The autonomic fibres are responsible for sweating and oil gland secretion. Sensation is affected on the lateral side of the forearm and the palmar side of the hand, thumb, index, middle, and half of the ring finger. It innervates the muscles of the hand and in leprosy affects predominately the intrinsic muscles of the thumb, making opposition and prehension difficult. Weakness and paralysis causes the thumb to be flat within the hand. |
| Motor fibres | Motor nerves (or efferent nerves), transmit impulses from the brain and spinal cord to the muscles. |
| Multibacillary | Having numerous bacilli. "Multibacillary leprosy" classification by World Health Organization for the purpose of treatment is a person with more than five lesions. |
| Paucibacillary | Having just a few bacilli. "Paucibacillary leprosy" classification by World Health Organization for the purpose of treatment is a person with five or fewer lesions. |
| Peripheral nerve | A vast transmission network of afferent and efferent nerves from the central nervous system (brain and spinal cord) distally to every other part of the body. The motor, sensory, and autonomic fibres have specific functions within the area innervated by the specific peripheral nerve. Nerves can be composed primarily of motor or sensory fibres or be mixed, having both motor and sensory fibres. |
| Peroneal nerve | The common peroneal divides into the superficial and deep peroneal branches. The deep branch innervates the muscles of the anterior compartment of the leg (anterior tibial muscle, the long extensor muscle of the big toe and the long extensor muscles of the toes). When weak or paralysed, it makes it difficult to lift the foot and toes as well as evert the foot when walking. In leprosy, it is frequently referred to as "foot drop". Its sensory fibres innervate the lateral dorsal surface of the lower leg and foot. The sensory fibres of the superficial branch provides sensation to the web space of the big toe and the medial surface of the second toe. |
| Tibial nerve | One of the two major divisions of the sciatic nerve, it courses down the back of the leg to terminate as the medial and lateral plantar nerves in the foot; it supplies the hamstring muscles, the muscles of the back of the lower leg, and the intrinsic muscles of the foot. It causes clawing of the toes if muscles are paralysed. It provides sensation to the back of the leg and sole of the foot. The sensory loss to the sole of the foot puts the foot at high risk for injury and ulceration. |
| Sensory fibres | Sensory nerves (or afferent nerves), carry information from the outside world, such as sensations of temperature (hot, cold), touch, texture and pain, to the brain and spinal cord. They alert the body to pleasant feelings as well as to danger. |
| Sural nerve | A sensory nerve in the calf region (sura) of the leg. It is made up of collateral branches of the tibial nerve and common fibular nerve. |
| Trigeminal nerve | The three‐branch trigeminal (fifth cranial) nerve innervating the face, eyes, nose, mouth, and jaws. The corneal sensory loss in leprosy can cause the eye to be at risk for increased dryness and corneal abrasions. |
| Ulceration | Formation or development of an ulcer. On the skin, it is a loss of epidermis, often part of the dermis and even subcutaneous fat layers of the skin. |
| Ulnar nerve in the upper extremity | It is composed of motor, sensory, and autonomic fibres. The autonomic fibres are responsible for sweating and oil gland secretion. Sensation is affected on the ulnar (medial) side of the forearm, hand, the palmar side of the 5th and half of the 4th fingers. It innervates the muscles of the hand and in leprosy affects predominately the distal intrinsic muscles used for fine motor tasks. Weakness and paralysis causes finger clawing. |
| Vasodilation | A widening of the blood vessels caused by a relaxation of the smooth muscle cells in the vessel wall. The sympathetic nervous system has nerves that play an important role in vasodilatation and vasoconstriction. |
Description of the condition
Leprosy (Hansen's disease) is a chronic infectious disease caused by the bacterium Mycobacterium leprae (M leprae) (Lockwood 2002a). Official figures show that just over 173,000 people were detected with leprosy in 2016, mainly in Asia, the Americas and Africa. The World Health Organization (WHO) stated that less than 14 countries reported more than 1000 new cases in 2015, suggesting that leprosy is gradually becoming limited to a small number of countries (WHO 2016). The WHO fact sheet on leprosy states that 216,108 people from 145 countries were taking medication for leprosy at the end of 2016 (WHO 2017).
Although the detection rate is declining slowly worldwide, it is rising in a few places (Mandavilli 2019). The proportion of children under 15 years of age among new cases of leprosy ranges widely between countries: from 0.8% to 38.1% in 2015 (mean 8.9%) (WHO 2016). The significant number of childhood cases shows that person‐to‐person transmission continues to be a problem and many people suffer from the consequences of leprosy (McDougall 2002). Numbers are based on the number of persons with visible impairments of the eyes, hands, and/or feet at the time of diagnosis (WHO disability grade 2). Over 14,000 new cases of leprosy in 2015 were diagnosed with grade 2 disability, which is 2.1 per million population (WHO 2016). In this report, the proportion of new cases with grade 2 disabilities ranged from 4.4% to 25.4%. The numbers of new leprosy cases with disability grade 2 increased from 12,392 in 2006 to 14,059 in 2015 (WHO 2016). The variation can be explained by the methods of detection and reporting in those countries. The low levels of grade 2 disabilities indicates improved disease awareness and early disease detection in communities and health systems. A total of 3039 relapses were reported from 103 countries in 2015 (WHO 2016).
South‐East Asia has the highest prevalence of leprosy (persons on leprosy treatment), followed by the Americas, Africa, the Western Pacific, Eastern Mediterranean and Europe. Of all those identified as having the disease, 60% live in India, 13% live in Brazil, and 8% live in Indonesia (WHO 2016).
Leprosy is treated with a combination of immunosuppressive and antibiotic drugs (multidrug therapy) Lockwood 2002a). The drugs are rifampicin, dapsone, and clofazimine, which are effective in killing the bacilli, but do not prevent or treat the nerve inflammation and damage. The inflammation and damage is caused by the immune system responses, requiring other interventions, such as corticosteroids, surgery, or both (Lockwood 2002a). The effectiveness of corticosteroids has been evaluated in a systematic review (Van Veen 2007), whilst surgery for treating nerve damage in leprosy was reviewed in another systematic review (Van Veen 2012). Virtually all people detected with leprosy should be registered with their local health services and treated with multidrug therapy (WHO 2013). People affected by leprosy who are or have been treated with multidrug therapy are not infectious (WHO 2010).
See Figure 1 for pictures of ulcers.
Examples of ulcers in patients with leprosy: (A) Blister formed after walking long distances that later became an ulcer. (B) Fissure on the base of the second toe of the right foot. (C) Right medial malleolus ulcer from a patient with leprosy and HBP. (D) Plantar ulcer on the region of second metatarsal head. (E) Myiasis in a chronic leg ulcer. (F) Chronic ulcer on a lower limb stump.
Pictures first appeared in Barreto 2010, with kind permission from Josafá Gonçalves Barreto.
Clinical manifestations and complications
Generally, leprosy starts with a patch or lesion on the skin and enlargement of nerves which may also damage peripheral nerves (Bell 1995; Lockwood 2002a). Often the first signs are a lighter colour patch of skin with loss of hair, sweating and a loss of sensation to temperature and touch and enlarged peripheral nerves when palpated. The principal manifestations are skin patches or lesions with loss of sensation (flat or raised red patches on the skin) and specific enlarged peripheral nerves. The number of lesions may range from one to many depending on a person's immunity. In those with a large number of bacteria, the skin may become diffusely thickened and dry and peripheral nerves enlarged. Inflammation of peripheral nerves can damage nerve function (autonomic, sensory, and motor) and may cause later complications (Bell 1995; Lockwood 2002a). Most complications are the result of nerve damage through direct invasion by the M leprae bacteria or inflammation caused by reactions of the person's immune system. If treated early, much of the nerve damage leading to problems in the face, hands, and feet can be prevented (Van Veen 2009).
Initially, the small sensory and autonomic nerve fibres in the skin are damaged, causing local loss of hair, inability to sweat and difficulty detecting temperature and touch sensations. Damage to peripheral nerves can lead to more widespread skin dryness, loss of sensation, and weakness or paralysis of muscles in areas of the body supplied by the affected nerve. The eyes, hands, and feet, with loss of sensation, paralysis and dryness, are at a higher risk of injury and require daily self‐care. The dry skin can lead to cracks. If cracks, injuries, and ulcerations are not cared for and rested, they can become infected and lead to further injury and destruction, resulting in visible damage and destruction of the eyes, hands, and feet. These are easily seen impairments; this destruction and paralysis are visible and commonly known as grade 2 disability in leprosy (Lockwood 2002a). If a new leprosy case is seen with a visible grade 2 disability (WHO 2013), then the diagnosis has been late. Community health education programmes, health systems, or both, need to explore strategies to improve early disease detection as well as early detection of nerve function loss and treatment.
The peripheral nerves may be enlarged and/or painful with or without loss of function (sensory loss or muscle weakness). Common enlarged nerves are the auricular nerve, facial nerve, radial cutaneous and ulnar cutaneous and ulnar nerve at the elbow, peroneal nerve, posterior tibial and sural nerves. Nerve palpation for enlargement and pain plus testing for sensory loss and muscle weakness are important parts of the routine clinical exam.
Peripheral nerve function is tested in the face by checking corneal sensation (trigeminal nerve) and eye closure weakness (facial nerve). Peripheral nerve function in the upper extremities evaluates sensory areas and muscle strength of areas innervated by the ulnar and median nerves. Peripheral nerve function in the lower limb evaluates sole sensory loss (posterior tibial nerve) and strength in raising the foot upwards towards the shin or dorsiflexion (peroneal nerve).
Major areas affected by nerve damage in leprosy are the hands (especially the palms), feet (especially the soles), and eyes (Lockwood 2002a). The main complication of sensory nerve damage and the loss of intrinsic muscle function is ulceration, particularly of the feet (de Win 2002; Lockwood 2002a). The multidrug therapy offered to people infected with M leprae is efficacious in killing the bacilli if given for a sufficient length of time of six to 12 months (WHO 2006). Even with treatment, some people with leprosy can have immune reactions during and after treatment that require immediate action to reduce the inflammation to prevent or minimise permanent secondary damage to skin and peripheral nerves. If the reaction is not identified and treated adequately, damage cannot be reversed (Lockwood 2002a; Van Veen 2009).
Late diagnosis is the greatest cause of disability, followed by reactions that happen before, during, and after treatment. Frequently, they are either not identified, not treated adequately, or both. It is assumed that for those with permanent nerve damage, further damage and complications may be reduced by good self‐care practices, the use of protective footwear, surgery, etc (Lockwood 2002a). Existing WHO 2011 guidelines emphasise the importance of preventing disabilities and mention "identify", "train", "support" and "integrate" as being important principles. Some strategies are suggested as follows (WHO 2011, page 11).
-
"Involve persons affected by leprosy to encourage individuals to go for early evaluation."
-
"Formally engage persons affected by leprosy in the promotion of self‐care and the identification of people in need of practising self‐care."
-
"Involve persons affected by leprosy in identifying individuals in need of aids and appliances such as protective footwear."
Successful rehabilitation is an important issue that can be achieved through a combination of efforts made by the community and the individuals with their families (WHO 2011). In September 2018, India's Supreme Court ruled that "the government must end discriminatory laws, conduct regular surveillance to detect new cases, provide treatment to everyone who needs it, and promote awareness of leprosy as a curable disease" (Mandavilli 2019).
Diagnosis
Leprosy is diagnosed clinically by the following principal signs (Lockwood 2002a):
-
skin lesions with a decrease in sensation, i.e. parts of the skin may feel numb and not able to detect temperature, touch, or painful stimuli such as a pin prick;
-
thickened (enlarged) peripheral nerves that can easily be felt through the skin; and/or
-
positive smear, i.e. evidence of the causative bacterium, M leprae, using microscopic examination of a sample of tissue (skin smear).
Skin biopsy is also used for the diagnosis (Singh 2011).
Classification
There are two main forms of classification (Lockwood 2002b): 1) the Ridley‐Jopling scheme; and 2) the WHO operational classification of paucibacillary/multibacillary classification.
Ridley‐Jopling scheme
This scheme classifies leprosy on a scale from 'tuberculoid' to 'lepromatous', based on the clinical appearance and bacterial index of lesions (Lockwood 2002b). 'Tuberculoid' indicates that the body's immunity is good and there are few skin lesions. 'Lepromatous' means that the body has a poor immune response to the mycobacteria, and there is uncontrolled bacterial multiplication, many skin lesions, and also lesions in the mucosa of the nose and mouth. Peripheral nerve damage can occur at any point on the scale. Between the extremes of 'tuberculoid' and 'lepromatous' are the 'unstable borderline tuberculoid' and 'borderline lepromatous' forms (Lockwood 2002b).
WHO operational classification
This classification is based on the number of skin lesions (Britton 2004):
-
paucibacillary ‐ up to five lesions
-
multibacillary ‐ more than five lesions (or a positive smear at any site).
This is a simple classification scheme that makes treatment simpler for field workers, but it is less specific than the Ridley‐Jopling scheme. The WHO operational classification system is the most widely used.
Impact
Nerve damage can happen before, during, and after chemotherapy treatment. It affects approximately 30% of people diagnosed with leprosy (2.6% with paucibacillary, 37% with multibacillary, 2 years after diagnosis and multidrug therapy treatment; Lockwood 2001). Data from 2002 showed that approximately 6% to 9% of people with newly‐diagnosed leprosy presented with grade 2 disabilities (visible deformity or damage present), and as many as 20% to 56% of people have established nerve damage at diagnosis (Lockwood 2002c). These figures vary from country to country and between disease types. Penna 2017 demonstrated the progression of impairments/disability in around 30% of participants after multidrug therapy completion.
Description of the intervention
Leprosy is treated with multidrug therapy. Other interventions, which we will not cover in this review, are aimed at treating immune reactions with corticosteroids, surgery, or both (Lockwood 2002a).
The interventions of relevance to this review are those used in leprosy care which are aimed at the prevention and/or treatment of secondary damage to skin, nerves, and limbs. Preventive interventions include information, education, footwear and self‐care. Foot soaks, Vaseline and wax therapy are also meant to prevent ulcers and skin changes. Interventions aimed at treating ulcers include footwear, dressings (i.e. zinc tape, saline, iodine, gauze soaked in different ointments, dry dressings), self‐care, information and education (Lockwood 2002a). Therapies like different ointments and gels for topical use; other dressings; and laser, light‐emitting diode (LED), or pulsed magnetic fields have been used in trials to aid healing of existing ulcers.
Usual care that aims to prevent ulcers might be information, education, footwear and self‐care. Usual care for people that have developed ulcer(s) could also be footwear, self‐care, dry dressings, or dressings with saline. Surgical interventions are not covered in our review.
How the intervention might work
The rationale behind the use of, for example, appropriate footwear is to protect feet from secondary damage that can lead to superficial sores on the soles of the feet, and later ulcers and secondary infections (McDougall 2002). Many other interventions have been tried in healing such ulcers (Srinivasan 1989).
Self‐care includes daily management to reduce the effects of nerve function impairment (Lockwood 2002a). Education, information, and empowerment of those affected by leprosy (and their carers) is part of some leprosy programmes (Cross 2005a; Cross 2005b; McDougall 2002).
As for dressings, phenytoin is a topical dressing thought to enhance cutaneous healing (Hokkam 2011). Zinc tape is also thought to enhance healing, as zinc might play a part in the healing of wounds. Over many years ordinary adhesive zinc tape has been used (Kumar 1986). Dry dressings and saline dressings are used to protect ulcers from contamination and thus enhance healing.
Adverse reactions to any dressings could be allergic or local irritation or pain associated with application or injection. Other adverse effects might be disadvantages related to time and resources for the person involved (hospitalisation, frequent visits to outpatient clinics, etc.).
Why it is important to do this review
The key to effective management of leprosy is early diagnosis and treatment, and early recognition and management of nerve damage, combined with effective health education to prevent limb damage (Lockwood 2002a; Lockwood 2002b). Successful treatment of nerve damage itself can be effective for preventing ulcer development. Corticosteroids have been used for this purpose (Lockwood 2002a). However, a systematic review of three RCTs comparing prednisolone with placebo or comparing different doses of corticosteroids did not show a statistically significant long‐term effect (Van Veen 2007). Also, corticosteroids are not well tolerated by everyone and may cause harmful effects (Lockwood 2002a). It is therefore still of importance to find the best way to prevent or treat skin damage.
People with leprosy are, after a few days on chemotherapy, no longer infectious and can lead a normal social life. This has contributed to the management of leprosy programmes worldwide moving away from clinics dedicated to the treatment of leprosy, to primary healthcare services in general (Lockwood 2002a; WHO 2010). Despite the opportunity to live a normal social life, long‐term nerve and muscle damage can lead to great psychosocial and financial difficulties, social stigmatisation, and decreased quality of life for people with leprosy. Care and awareness of limb use will in all circumstances be necessary, and education of those with leprosy is considered a central element to achieve a satisfactory level of self‐care (Lockwood 2002a).
Why we presented a new protocol
When we made the decision to update our review from 2008 (Reinar 2008), we wanted to do this by way of a new protocol. In the new protocol the numbers of prespecified outcomes were reduced to those that are most clinically relevant, and it includes both RCTs and quasi‐RCTs.
We included RCTs and quasi‐RCTs where the method of allocation was such as alternation, date of birth, or case record number (Higgins 2011). This deviates from the previous protocol (Reinar 2003). In our published review (Reinar 2008), we identified and included three studies with an alternating allocation procedure, four studies reported as RCTs, and one study for which we could not determine whether the allocation procedure had been random or quasi‐random.
The reason for including quasi‐randomised trials was that the risk of bias is not necessarily very different. According to Altman and Bland, quasi‐random methods are "in principle unbiased ‐ being unrelated to patients' characteristics ‐ problems arise from the openness of the allocation system" (Altman 1999). This point was elaborated in Chalmers 1999. As for RCTs, the results from a study by Pildal 2005, revealed that of 96 studies not reporting on the concealment of the allocation procedure, only 15 (16%) actually had reported in the respective study protocols that concealment would be done. In the randomised studies that we included, none reported on concealment. On this basis, we assumed that most likely the randomised studies had not concealed allocation and so did not deviate from quasi‐randomised trials in that respect. Consequently, they would all be prone to selection bias. Therefore, we chose to display the whole of the evidence base that had used these two designs, a decision we affirmed in the protocol.
Objectives
To assess the effects of education, information, self‐care programmes, dressings, skin care, footwear and other measures for preventing and healing secondary damage to the skin in persons affected by leprosy.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials (RCTs), quasi‐RCTs, and randomised cross‐over trials. We did not include observational studies. Quasi‐RCTs were defined as trials with an allocation procedure such as alternation, date of birth or case record number.
Types of participants
People with leprosy and potential damage to peripheral nerves who were on multidrug treatment or were post‐treatment. We considered studies that included participants living in the community or those that were hospitalised. Case definitions were typically based on the Ridley‐Jopling scheme or the World Health Organization (WHO) operational classification of paucibacillary/multibacillary classification. However, we also included studies that did not specify the diagnostic criteria. We included studies with participants of all ages, genders, all countries, and all kinds of ulcers caused by leprosy. Studies with a subset of leprosy participants would have been included if they constituted more than 90%.
Types of interventions
Education, information, self‐care programmes, dressings (i.e. zinc tape, saline, iodine, gauze soaked in different ointments, dry dressings), skin care, footwear, or other measures designed to prevent or treat damage.
Comparisons might be usual care, no interventions, or other interventions (for example, other types of dressings, other types of footwear, other measures designed to prevent or treat damage). Interventions could be given in primary care, outpatient units, or in hospitals.
Types of outcome measures
Primary outcomes
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Prevention of ulcer(s), as measured in the studies at typically six weeks or less, up to three months, six months, or one year or more.
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Healing of existing ulcer(s), as measured in the studies at six weeks or less, up to three months, six months, or one year or more (e.g. number of ulcers healed, size of ulcers, number of new ulcers).
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Adverse events, either those sufficiently serious to stop the intervention, or minor ones reported by participants.
Secondary outcomes
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Quality of life measures or other psychological or functional measures.
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Acceptability of treatment by person affected by leprosy, as measured in the studies.
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Cost of intervention, as direct costs, if reported by study authors.
Tertiary outcome
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Prevention or treatment of other skin changes, such as cracking, thickening or pigmentary changes.
Search methods for identification of studies
We aimed to identify all relevant RCTs regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
For this update, we revised all our search strategies in line with current Cochrane Skin practices. Details of the previous search strategies are available in Reinar 2008.
The Cochrane Skin Information Specialist searched the following databases up to 25 July 2018.
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Cochrane Skin Group Specialised Register using the search strategy in Appendix 1.
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Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 6), in the Cochrane Library using the strategy in Appendix 2.
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MEDLINE via Ovid (from 1946) using the strategy in Appendix 3.
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Embase via Ovid (from 1974) using the strategy in Appendix 4.
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CINAHL (Cumulative Index to Nursing and Allied Health Literature) (EBSCO) using the strategy in Appendix 5.
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AMED (Allied and Complementary Medicine Database) using the strategy in Appendix 6.
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LILACS (Latin American and Caribbean Health Science Information Database) using the strategy in Appendix 7.
Trial registers
We (LF, LMR) searched the following trial registers for ongoing trials using the term 'lepro*' up to 24 February 2019.
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ISRCTN registry (www.controlled‐trials.com).
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ClinicalTrials.gov (www.clinicaltrials.gov).
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Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
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World Health Organization International Clinical Trials Registry Platform (ICTRP) (apps.who.int/trialsearch/).
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EU Clinical Trials Register (www.clinicaltrialsregister.eu/).
Searching other resources
Grey literature
We (LF, LMR) searched for grey literature to identify studies not indexed in the databases listed above, using the following databases up to 24 February 2019.
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OpenSIGLE (www.opengrey.eu) (search phrase: leprosy and ulcer*).
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OAIster (www.oclc.org/oaister) (search phrase: kw:leprosy ti:leprosy ulcer*).
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Grey Literature Report (www.greylit.org) (search phrase: leprosy).
References from published papers
We checked the bibliographies of included studies and identified reviews for further references to relevant trials.
We did not search for unpublished and ongoing trials by corresponding with authors, field experts, or experts on tropical medicine or leprosy or both (deviation from protocol).
Adverse effects
We did not perform a separate search for adverse effects of the target interventions. We considered adverse effects described in the trials we read in full text only. We considered all adverse effects reported in the included trials.
Data collection and analysis
Some parts of the methods section of this review use text that was originally published in other Cochrane Reviews co‐authored by KGB (predominantly Larun 2015).
Selection of studies
Two review authors (LMR, LF) independently screened all titles and abstracts identified in the literature searches for RCTs and quasi‐RCTs. We excluded studies that clearly did not have a trial design with random or quasi‐random allocation of participants. Before inclusion or exclusion, the same two review authors independently read the full text of studies that we assessed as eligible. At this point, we discussed any disagreement with a third review author (KGB), and decisions were made by consensus. We made judgements based on the inclusion criteria stated above (Criteria for considering studies for this review).
Data extraction and management
Two review authors (LMR, LF) independently performed the data extraction and entered data onto a data extraction form. One author (LMR) entered data into Review Manager (Review Manager 2014), and one review author (LF) checked the Review Manager file. We were not blinded to the names of trial authors or journals. We used the same piloted data extraction form that we used for our previous review (Reinar 2008). The data items we extracted were title, country where study took place, type of study, type of participants, type of interventions, control group interventions, setting, number of eligible participants, number entered into each study group, demographical data of participants, primary and secondary outcomes, results, unit of allocation, unit of analysis and length of follow‐up.
Assessment of risk of bias in included studies
We (LMR, LF) used Cochrane's 'Risk of bias' tool to make judgements of low, high, and unclear risk of bias for all included studies for all outcomes (Higgins 2011). We discussed any disagreement with a third review author (KGB), and decisions were made by consensus. We also presented the review authors' judgement about each 'Risk of bias' item presented as a percentage across all included studies as a 'Risk of bias' graph (Figure 2).
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
We assessed selection bias by judging and reporting methods used for sequence generation and allocation concealment. Quasi‐randomised trials were judged as 'high risk of bias' regarding sequence generation and unclear for concealment of allocation. Randomised trials not reporting on allocation concealment were judged as 'unclear'. We assessed performance bias by judging and reporting any blinding of participants, personnel, and outcome assessors. We also looked for and reported any other threats to validity concerning systematic differences between groups in the care provided. We assessed detection bias by judging and reporting any blinding of participants, personnel, and outcome assessors. We assessed attrition bias by looking for systematic differences in loss to follow‐up between groups. We also looked for and reported other potential threats to validity concerning systematic differences between groups in how outcomes were determined. We assessed reporting bias (selective outcome reporting) by examining the protocol or methods section of the included study for mention of outcomes that were not reported later in the study or for outcomes that would have been expected to have been measured. If our search had identified study protocols we would have used these in the assessment of potential publication bias. We assessed other risks of bias by judging and reporting, for example, avoidance of cointerventions, differences in baseline characteristics, recruiting bias, or inappropriate influence of funder. We did not exclude studies at high risk of bias.
We summarised 'Risk of bias' assessments for each key outcome for each study in a 'Risk of bias' summary table (Figure 3).
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Measures of treatment effect
Dichotomous data
Effect estimates based on dichotomous data were reported as risk ratios (RRs) with 95% confidence intervals (CIs).
Continuous data
We calculated continuous outcomes as mean differences (MD) with 95% CIs.
If different scales had been used for the same outcome, we would have calculated standardised mean differences (SMDs) to allow pooling. Studies which reported change data would have been pooled with studies using post‐test data in the same meta‐analysis, with change data and endpoint data as subgroups.
Unit of analysis issues
Cluster‐randomised trials
Unit of analysis errors may occur if analyses are conducted on a different level to the allocation. Authors of cluster‐randomised trials may fail to account for the intraclass correlation coefficient (ICC), leading to a 'unit of analysis' error; whereby CIs are unduly narrow and statistical significance overestimated (Divine 1992). If we had included a cluster‐randomised trial and clustering had not been accounted for in primary studies, we would have contacted the corresponding author to obtain the ICC, if we thought it would make a difference to the results. In that case, we could have adjusted for this by using methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) (chapter 16.3). If cluster studies are appropriately analysed taking into account the ICC, and relevant data are reported, synthesis with other studies will be possible using the generic inverse variance technique. In that case, we would have presented data adjusted for the clustering effect as if from a parallel‐group randomised study, but we would have performed sensitivity analysis in which such studies would have been excluded.
For this update, we did not identify any cluster‐randomised trials. However, since some trials randomised participants of which some had several ulcers, there is for these studies, an element of clustering. In principle, this should have been accounted for in the analysis. In the studies that explicitly included people with several ulcers without reporting how this was handled in the analysis, we made a note of this in the Characteristics of included studies table. However, we judged that the clustering was not comprehensive enough to make any difference to the reported results.
Multiple levels of intensity
One study may address the effects of the same intervention with multiple levels of intensity (e.g. frequency of follow‐up). In that case, for dichotomous outcomes we would have summed up the sample sizes and the number of people with events across all relevant intervention groups. For continuous outcomes, we would have combined means and standard deviations using methods described in chapter 7 (section 7.7.3.8) of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
Multiple interventions
Studies may also combine several interventions with one comparison group. We did not identify any studies with multiple interventions. In that case, we would have analysed the effects of each intervention group versus the comparison separately, but divided the total number of participants in the comparison group. In the case of continuous outcomes the total number of participants in the comparison group would also have been divided, but the means and standard deviations would have been left unchanged (see chapter 16, section 16.5.4 in Higgins 2011).
Randomised cross‐over trials
If we had found and included randomised cross‐over trials we would have analysed data from the first period only.
Dealing with missing data
We planned to carry out analyses of all outcomes of interest according to the participants' allocated treatment, irrespective of whether they received that treatment or not. However, some studies had loss to follow‐up of participants. In these cases, we did not attempt to impute missing data.
For studies published in the previous 10 years, we contacted two trial authors to ask for data and more information, but neither of them responded.
Assessment of heterogeneity
When we judged that the included trials were too clinically heterogeneous to warrant a formal meta‐analysis, we did not perform a meta‐analysis, but presented the results of the included trials in a narrative format.
In the case of a meta‐analysis, we would have assessed statistical heterogeneity on the basis of the Cochrane Handbook for Systematic Reviews of Interventions recommendations: I² values of 0% to 40% might not be important; 30% to 60% may represent moderate heterogeneity; 50% to 90% may represent substantial heterogeneity; 75% to 100% may represent considerable heterogeneity (Higgins 2011).
In addition to the I² value (Higgins 2011), we would have presented the Chi² statistic and its P value and considered the direction and magnitude of the treatment effects. The Chi² test is underpowered to detect heterogeneity in meta‐analyses with few studies (Higgins 2011), and hence a P value of 0.10 would have been used as a threshold of statistical significance.
Assessment of reporting biases
We attempted to obtain unpublished results to minimise the risk of reporting bias. There were too few studies in each comparison to perform funnel plots to identify publication bias.
Data synthesis
We presented the results of trials we assessed to be too heterogeneous to combine in a narrative format. The results of single studies are illustrated in forest plots for visualisation. In a meta‐analysis we would have estimated the effect across studies by using a random‐effects model because we would have expected some clinical heterogeneity (slightly different interventions, populations and comparators) among studies. Where results are estimated for individual studies with low numbers of outcomes (< 10 in total) or where the total sample size is less than 30 participants and a risk ratio is used, we also reported the proportion of outcomes in each treatment group together with a P value from a Fisher's exact test (Higgins 2011). We created the forest plots using Review Manager 5 (Review Manager 2014).
Subgroup analysis and investigation of heterogeneity
We did not have sufficient data to undertake subgroup analyses according to the study's classification of disease severity.
Sensitivity analysis
No study results were pooled in this review. Accordingly, we could not perform sensitivity analysis for pooled results separately by addressing the effects on the results of excluding:
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studies assessed as being at high risk of bias;
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quasi‐randomised trials; and
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cluster‐randomised trials.
'Summary of findings' table
We (LMR, LF) used the GRADE approach to assess the certainty of the body of evidence (GRADE Handbook 2013). We produced 'Summary of findings' tables presenting the overall certainty of evidence for primary and secondary outcomes for each comparison. The outcomes reported in our 'Summary of findings' tables are as follows.
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Prevention of ulcers
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Healing of ulcers
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Adverse events
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Quality of life
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Acceptability of treatment
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Costs
We used GRADEpro to prepare the 'Summary of findings' tables (GRADEpro GDT 2018). We judged the following domains in all included studies: study design, risk of bias, inconsistency, indirectness, imprecision and other considerations. We made an overall assessment of the certainty of the evidence as high, moderate, low, and very low (Higgins 2011, chapter 11). Any disagreements were discussed with a third review author (KGB) and were resolved by reaching consensus.
Results
Description of studies
See Characteristics of included studies.
Results of the search
The searches for this update identified 2093 citations to potentially relevant new trials. We excluded 2051 references based on titles and abstracts. We identified two relevant ongoing studies (CTRI/2012/12/003178; NCT03072004; see Characteristics of ongoing studies). We assessed the remaining 40 records in full text, and excluded 34 (Characteristics of excluded studies). We included six new studies, along with eight studies from the previous review, which brought the total number of included studies to 14 (Characteristics of included studies). See the study flow diagram for a summary of the screening process (Figure 4).
Study flow diagram.
Included studies
Design
We included 14 trials (randomised and quasi‐randomised) with a total of 854 participants. The studies were published between 1982 and 2018. Two studies had three arms, and one study reported on two separately conducted trials (multicentre study). The initial assessment and baseline reporting of leprosy and damage to peripheral nerves was recorded in varying details, as was the reporting of outcome measurements and results.
Sample sizes
All included trials were small, with between 25 and 110 adult participants affected by leprosy.
Participants
In 12 of the studies, all participants had ulcers at trial entry. In one study (Seboka 1998), some of the participants had scars, not ulcers. One study only included participants with anaesthetic feet with fissures or callosities, or both (Sharma 2005). The participants were aged between 18 and 74 years, but age was not reported in four studies (Pring 1982; Sharma 2005; Söderberg 1982; Walton 1986). Gender was not reported in three studies (Pring 1982; Sharma 2005; Walton 1986), but information from the remaining studies suggests there were more men amongst the participants (472 men and 157 women).
All studies except Sharma 2005 included participants affected by leprosy with plantar ulcers, and three studies also included participants with ulcers elsewhere, mostly the hands (Bansal 1993; Lee 2012; Salazar 2001). The majority of participants had only one wound (ulcer) on one foot. The wounds were mainly simple (not infected) and they varied in size and depth; some wounds were more complicated. The majority of participants had their wounds for less than a year.
Setting
The trials took place in Brazil, Ethiopia, Egypt, Indonesia, Mexico, South Korea, and most in India. Four studies were hospital based (Bansal 1993; Bhatia 2004; Sharma 2005; Söderberg 1982), while nine were based at outpatient clinics (Barreto 2010; Overbeek 1991; Prakoeswa 2018; Pring 1982; Salazar 2001; Seboka 1998; Sarma 1997; Mikhael 2015; Walton 1986). One study included both in‐ and outpatients (Lee 2012).
Interventions
The studies evaluated various treatment interventions: low laser therapy (3 times per week) (Barreto 2010), light‐emitting diode (LED; 20 minutes) (Lee 2012), weekly injected intralesional pentoxifylline (Mikhael 2015), daily to weekly zinc tape (Overbeek 1991; Söderberg 1982), zinc tape in addition to self‐care and sandals (Walton 1986), padded moulded double‐rocker plaster shoe (in addition to education) (Pring 1982), topical ketanserin (every 12 hours) (Salazar 2001), topical human amniotic membrane‐mesenchymal stem cell‐conditioned medium (every 3 days) (Prakoeswa 2018), daily pulsed magnetic fields (in addition to self‐care and protective footwear) (Sarma 1997), PVC boots (daily) (Seboka 1998), daily wax therapy (Sharma 2005), and daily topical phenytoin dressings (Bansal 1993; Bhatia 2004).
Comparisons
Nine of the interventions were compared to dry dressings or dressings soaked in differing solutions. Padded, moulded double‐rocker plaster shoes were compared to padded below‐knee plasters, which were the traditional method; PVC boots were compared to canvas shoes; and hot wax therapy was compared to 20 minutes foot soak in water plus Vaseline.
Duration
Four interventions were given for four weeks (Bansal 1993; Bhatia 2004; Sarma 1997; Walton 1986), three were given for six weeks (Pring 1982; Overbeek 1991; Sharma 2005), three were given for eight weeks (Mikhael 2015; Prakoeswa 2018; Söderberg 1982), two were given for 12 weeks (Barreto 2010; Salazar 2001), and one intervention was given for 12 months (Seboka 1998). Lee 2012 did not report duration of treatment period, but the whole study lasted eight months.
Outcomes
All trials but one reported as the primary outcome 'Healing of existing ulcers', measured either as proportion healed or number of ulcers healed. Adverse events were covered in a few trials, but there was limited information on how this outcome was measured. Costs were not systematically assessed, and neither were acceptability of treatment nor any quality of life measures. The follow‐up period from baseline varied from one month to one year. The follow‐up period did not, in any trials, go beyond the study duration, and outcomes were measured either during the trials or at the end of study duration, or both.
Typical outcome measures were number of ulcers healed, size of ulcers or reduction of ulcer size, number of new ulcers, ulcer‐free at one year, ulcers not healed, ulcers fully healed, and use of adapted footwear.
None of the 14 included studies measured quality of life. Prevention of ulcers was only reported in Seboka 1998. Only one study measured our tertiary outcome: prevention or treatment of other skin changes, such as cracking, thickening or pigmentary changes (Sharma 2005).
Funding sources
The included studies were funded by trusts, universities, research councils, leprosy trusts, and government grants. However, the majority of studies did not report funding source (Characteristics of included studies).
Excluded studies
We excluded 34 of the studies we read in full text (Characteristics of excluded studies). The main reason for exclusion was that they were not randomised trials (21 studies), they did not have a relevant intervention (7 studies), or publication type (being reviews or an editorial; 6 studies). One controlled trial evaluated wax therapy for dry feet (Mahajan 1995), but was not included because the allocation procedure seemed to be neither random nor quasi‐random.
Risk of bias in included studies
We assessed all studies for risk of bias (Characteristics of included studies). Due to generally poor reporting it was often difficult to make the assessments; hence, we rated many assessments at unclear risk of bias. We rated seven studies at high risk of bias in at least one domain including selection bias (random sequence generation) (Bansal 1993; Overbeek 1991; Söderberg 1982), attrition bias (Bhatia 2004; Overbeek 1991; Sarma 1997; Walton 1986). We did not consider any studies to be at low risk of bias for all domains. Please see Figure 2 for the 'Risk of bias' summary: review authors' judgements about each domain for each included study, and see Figure 3 for the 'Risk of bias' graph: review authors' judgements about each domain presented as percentages across all included studies.
Allocation
We judged three trials to be clearly quasi‐randomised and we rated these at high risk of selection bias from random sequence generation (Bansal 1993; Overbeek 1991; Söderberg 1982). Two trials were potentially quasi‐randomised (Salazar 2001; Walton 1986), but as we were not sure, we assessed them as having unclear randomisation procedures along with four other studies (Lee 2012; Pring 1982; Sarma 1997; Seboka 1998). We assessed five studies as having adequate randomisation sequence generation (Barreto 2010; Bhatia 2004; Mikhael 2015; Prakoeswa 2018; Sharma 2005). We considered all studies at unclear risk of selection bias regarding allocation concealment due to limited information reported in the publications.
Blinding
Although participants in many cases could have been blinded to their intervention, this was usually not described or reported in the included trials. Two studies reported that the patient and health care providers as well as the outcome assessor were blinded and we accordingly considered these as having low risk of performance and detection bias (Bhatia 2004; Sarma 1997), while Bansal 1993 reported only blinding of outcome assessor (low risk of detection bias). We considered the remaining studies as having unclear risk of performance and detection bias.
Incomplete outcome data
We had some concerns about attrition bias in four studies mainly due to loss of follow‐up (Bhatia 2004; Overbeek 1991; Sarma 1997; Walton 1986); therefore, we considered these studies at high risk of attrition bias. We rated one study as unclear on attrition bias (Söderberg 1982) and we considered the remaining studies at low risk of attrition bias.
Selective reporting
We have no reason to suspect any selective reporting in the studies. However, for all but one study we did not have access to the study protocols (Barreto 2010), but we did inspect the methods section in each study. We assessed all studies as having low risk of selective reporting.
Other potential sources of bias
We considered seven studies to be at unclear risk of other biases. Five studies randomised some participants with more than two ulcers (Bansal 1993; Barreto 2010; Pring 1982; Salazar 2001; Walton 1986), but the average cluster size was so small (less than 1.5) that the potential impact of a unit of analysis error was negligible. Hence, we considered these at unclear risk of other biases. Another study did not report clearly the number of feet included in the analyses, so we also considered this study at unclear risk of other biases (Sharma 2005). There was a unit of analysis error (90 participants with 128 ulcers) in Söderberg 1982. There was also a difference between hospitals in the proportion of participants who wore shoes in this study which might influence the results.
We considered the remaining seven studies to be at low risk of other biases.
Effects of interventions
See: Summary of findings for the main comparison Zinc tape compared to magnesium sulphate glycerin for ulceration caused by nerve damage in leprosy; Summary of findings 2 Zinc tape compared to povidone iodine (10%) for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 3 Adhesive zinc tape compared to gauze soaked in eusol for ulceration caused by nerve damage in leprosy; Summary of findings 4 Topical ketanserin (2%) compared to clioquinol cream (3%) or zinc paste for ulceration caused by nerve damage in leprosy; Summary of findings 5 Topical phenytoin compared to saline dressing for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 6 Footwear ‐ canvas shoes compared to PVC boots for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 7 Padded moulded double‐rocker plaster shoe compared to padded below‐knee plaster for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 8 Exposure to pulsed magnetic fields (in addition to self‐care and protective footwear) compared to self‐care and footwear for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 9 Low‐level laser therapy compared to simple dressing for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 10 Intralesional pentoxifylline compared to daily simple dressing for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 11 Light‐emitting diode (LED) irradiation compared to conventional dressing therapy for ulceration and other skin changes caused by nerve damage in leprosy; Summary of findings 12 Wax therapy compared to foot soaks for skin changes caused by nerve damage in leprosy; Summary of findings 13 hAMMSC‐CM + vitamin C compared to hAMMSC‐CM for ulceration caused by nerve damage in leprosy; Summary of findings 14 hAMMSC‐CM + vitamin E compared to hAMMSC‐CM for ulceration caused by nerve damage in leprosy; Summary of findings 15 hAMMSC‐CM + vitamin E compared to hAMMSC‐CM + vitamin C for ulceration caused by nerve damage in leprosy
None of the 14 included studies measured quality of life (secondary outcome). Prevention of ulcers (primary outcome) was only reported in Seboka 1998. Only one study measured our tertiary outcome (prevention or treatment of other skin changes such as cracking, thickening or pigmentary changes) (Sharma 2005).
Interventions for people with leprosy and existing ulcer(s)
Zinc tape compared to magnesium sulphate/glycerin
One study with 28 participants evaluated the effect of zinc tape versus sulphate/glycerin (Walton 1986), but the number of healed ulcers (primary outcome) was higher with zinc tape after one month; however, the 95% confidence interval (CI) included 1, showing some uncertainty (risk ratio (RR) 2.00, 95% CI 0.43 to 9.21; Analysis 1.1; Fisher's exact test P = 0.65; 4/14 versus 2/14 participants). In addition, the mean ulcer area was smaller in the zinc tape group (mean difference (MD) ‐14.30 mm², 95% CI ‐26.51 to ‐2.09; Analysis 1.2). We judged the evidence to be of very low certainty and accordingly have very little confidence in the effect estimate. We downgraded due to study limitations (such as 35% loss to follow‐up, consecutive cases were randomly allocated, no blinding of outcome assessor, and potential unit of analysis error. We also downgraded for imprecision due to sparse data and wide CIs. The study authors did not report adverse events, acceptability of treatment or costs. See summary of findings Table for the main comparison.
Zinc tape compared to povidone iodine
One study (Overbeek 1991), with 38 participants evaluated the effect of zinc tape versus povidone iodine (10%) on healing of ulcers (primary outcome). The authors did not detect a clear difference in the mean reduction of ulcer area at six weeks between the two groups because the result was highly imprecise (MD 128.00 mm², 95% CI ‐110.01 to 366.01; Analysis 2.1). We judged the evidence to be of very low certainty, and consequently we have very little confidence in the effect estimate. We also downgraded due to study limitations (quasi‐randomised trial, high loss to follow‐up, and no reporting of blinding of outcome assessor), and due to imprecision (1 study, few participants, wide CI). The study authors did not report prevention of ulcers, adverse events, acceptability of treatment or costs. See summary of findings Table 2.
Zinc tape compared to gauze soaked in Eusol
One study with 90 participants evaluated the effect of applications of zinc or gauze soaked in Eusol on healing of ulcer(s) (primary outcome) after one month (Söderberg 1982); the results were extracted from a figure in the publication. The participants had a total of 128 plantar ulcers. The average healing time was shorter for the group treated with zinc tape. The results varied between the two hospitals involved. In one hospital it took about 20 days (95% CI 18 to 23) for superficial ulcers to heal in the zinc tape group versus about 30 (95% CI 27 to 33) in the gauze group. For deep ulcers the average healing time was two weeks more. In the other hospital the average number of days to heal in the zinc tape group for superficial wounds were about 13 (95% CI 9 to 15) days and 23 (95% CI 16 to 28) days in the gauze group. For deep ulcers it took 17 days (95% CI 12 to 20) in the zinc tape group and 30 (95% CI 21 to 63) in the gauze group. There was a lack of information on how many participants and how many ulcers (deep or superficial ulcers) there were in the intervention and control group. We judged the evidence to be of very low certainty and have very little confidence in the reported results. For adverse events, the study authors reported that there were no signs of skin sensitisation in either group. We downgraded due to study limitations (allocation random alternate basis, no blinding of outcome assessor, and inadequate reporting of data), and due to imprecision (few participants). No signs of adverse events (skin sensitisation ‐ primary outcome) were observed. In terms of acceptability of treatment and costs, the authors reported that the zinc tape had a shorter healing time, lower cost, easier application and was more convenient for participants, and that it could be worn under shoes without causing pressure and was socially more acceptable with no bandages needed. However, it was not clear how the study measured these findings and no further data were reported. See summary of findings Table 3.
Topical ketanserin (2%) compared to clioquinol cream (3%) or zinc oxide paste
One study with 66 participants evaluated the effect of topical ketanserin (2%) versus clioquinol cream (3%) or zinc oxide paste (Salazar 2001), and showed a benefit of topical ketanserin on the 'risk' of ulcer healing (primary outcome) (RR 6.00, 95% CI 1.45 to 24.75; Analysis 3.1) after three months. We judged the evidence to be of very low certainty and have very little confidence in the effect estimate. We downgraded due to study limitations (randomisation procedure not reported, blinding not reported, and unclear if appropriate statistical analysis used) and due to imprecision (1 study, very wide CI). The authors reported that treatment was not suspended in any of the participants due to adverse events (primary outcome) (very low‐certainty evidence), study limitations (randomisation procedure not reported, blinding not reported), indirectness (not clear how side effects were measured and reported), or due to imprecision (1 study). The study authors did not report acceptability of treatment or costs. See summary of findings Table 4.
Topical phenytoin (2% or 4%) compared to saline dressing, and topical 4% phenytoin versus 2% phenytoin
Two studies with a total of 123 participants at inclusion evaluated the effect of topical phenytoin versus saline dressing on healing of ulcer(s) (primary outcome) at four weeks (Bansal 1993; Bhatia 2004). Bansal 1993 alternately assigned 50 participants to a phenytoin group and 50 to a saline group. The dose of phenytoin was not reported. Ten participants had two ulcers each and for these, one ulcer was treated with phenytoin and one with saline. The authors reported that MD in percentage ulcer volume reduction at four weeks were 16.60% (95% CI 8.46 to 24.74) (Analysis 4.1). The other study made three comparisons: both 2% and 4% phenytoin were compared to saline dressings and 4% phenytoin was compared to 2% phenytoin (Bhatia 2004). The outcome was mean percentage reduction of ulcer size area. In the comparison of 2% phenytoin with saline dressings, the ulcers of 23 participants out of the 30 included, were measured. MD in percentage reduction at four weeks was 39.30% (95% CI 25.82 to 52.78) in favour of the 2% phenytoin group (Analysis 5.1). Bhatia 2004 also compared 4% phenytoin to saline dressings. The intervention group had 15 participants included and of these the ulcers of five participants were measured (Bhatia 2004). MD in percentage reduction of ulcer size area between groups was 40.90 (95% CI 27.69 to 54.11) (Analysis 6.1). However, the number of participants in the table are not consistent with those given in the text. In the text it stated that the ulcers of 11 participants in both phenytoin groups, i.e. 2% and 4%, had healed, which means that the ulcers of 11 participants must have been measured. Regarding the third comparison in Bhatia 2004, 4% compared to 2% phenytoin, the MD between groups in percentage reduction of ulcer size area was 1.60% (95% CI ‐12.05 to 15.25) (Analysis 7.1). No adverse effects (primary outcome) were observed in any of the participants treated with phenytoin or normal saline.
As we do not know which solution of phenytoin Bansal 1993 used we could not pool the results. We judged the evidence for the results of these comparisons to be of very low certainty and consequently, we have very little confidence in the effect estimates. We downgraded due to study limitations (1 study was not adequately randomised and potentially had unit of analysis error (Bansal 1993), attrition bias (Bhatia 2004), and no information on allocation concealment) and imprecision (wide CIs (both studies)). The study authors did not report acceptability of treatment or costs. See summary of findings Table 5.
Footwear ‐ canvas shoes compared to PVC boots
One study, with a total of 110 participants (farmers in Ethiopia), evaluated the effect of canvas shoes versus PVC boots on number of persons being ulcer‐free at one year (Seboka 1998). Of the 110 participants, 38 had ulcers at baseline, thus the study evaluated both prevention of ulcers (primary outcome) and healing of ulcers (primary outcome). Seventy‐two participants had scars (not ulcers) at the start of the study (27 in the canvas group, 45 in the PVC group) and none of these developed new ulcers during the year. In the 38 participants who had ulcers at baseline, there was little or no difference between groups in the number of people with healed ulcers at one year (RR 1.16, 95% CI 0.77 to 1.74; Analysis 8.1). They also reported the number of persons having ulcers not healed after one year (RR 0.52, 95% CI 0.15 to 1.75; Analysis 8.2; Fisher's exact test P = 0.41; 4/25 versus 4/13 participants). The width of the CIs around the effect estimates for both outcomes makes the results inconclusive. Amongst the 110 participants, none developed new ulcers (only one was lost to follow‐up). They also reported on adverse events that PVC boots could become very hot in strong sunlight, with the possibility of burning feet. We judged the evidence to be of very low certainty and have very little confidence in the result. We downgraded due to study limitations (unclear randomisation, unclear blinding) and due to imprecision (1 study, wide CI).
On acceptability of treatment (secondary outcome) the study authors reported that the canvas shoes were socially acceptable, but 85% of the farmers rated them as good for their work, rather than "excellent" (8%) at first follow‐up at three months. The study authors reported that PVC boots were well liked and not stigmatising. We are moderately confident in this result, and have downgraded due to imprecision (1 study). Costs were not reported, but the study authors state that canvas shoes and PVC boots cost the same and that PVC boots are more durable than canvas shoes. See summary of findings Table 6.
Padded moulded double‐rocker plaster shoe compared to padded below‐knee plaster
One study with a total of 47 participants, with a total of 55 ulcers, evaluated the effect of padded moulded double‐rocker plaster shoe versus padded below‐knee plaster on ulcers healed (primary outcome) or nearly healed after six weeks (Pring 1982). The authors reported an effect size of RR 0.96 (95% CI 0.77 to 1.19; Analysis 9.1). We judged the evidence to be of very low certainty and have very little confidence in the effect estimate. We downgraded due to study limitations (no information on baseline characteristics; unit of analysis is ulcers, not participants; unclear randomisation procedure; unclear if blinding of outcome assessor), and due to indirectness (padded moulded double‐rocker plaster shoe and padded below‐knee plasters might not be acceptable interventions today for people with leprosy), and due to imprecision (1 study, small number of participants). The authors reported acceptability and cost (secondary outcomes), but gave no information on how they were measured. They stated that the plaster shoes were more acceptable to persons with leprosy, and that the below‐knee plaster immobilises the foot more. The moulded double‐rocker plaster shoe is also cheaper. Adverse events were not reported. See summary of findings Table 7.
Pulsed magnetic fields (in addition to self‐care and protective footwear) compared to self‐care and footwear
One study with a total of 40 (7 excluded during study) participants evaluated the effect of pulsed magnetic fields (in addition to self‐care and protective footwear) compared to self‐care and footwear on healing of ulcers (primary outcome) at four to five weeks (Sarma 1997). 'Pulsed magnetic fields' are low‐frequency, low‐intensity pulsed magnetic fields inducing no significant heating of the tissue. The authors reported in the control group that the geometric mean volumes of the ulcers were 2843 cu mm³ and 1478 cu mm³ on the day of admission and at the end of treatment (P = 0.03); the corresponding values in the pulsed magnetic field group were 2428 cu mm³ and 337 cu mm³, respectively (P < 0.001). A decrease in the volume of 40% or more was observed in 53% of control participants and 89% of pulsed magnetic field participants (P = 0.02): a decrease of 80% or more was observed in none of the controls and in 33% of pulsed magnetic field participants. The difference in ulcer volumes between the two treatment strategies did not reach statistical significance (MD ‐1.14 cm³, 95% CI ‐5.37 to 3.09; Analysis 10.1). We judged the evidence to be of very low certainty, and have very little confidence in the effect estimate. We downgraded due to study limitations (unclear randomisation procedure, 7 of 20 participants excluded) and due to imprecision (1 study with few participants). The authors reported the costs (secondary outcome) of the equipment used: "The cost of construction of an enclosure is around Rs. 5000/‐ (about 150 USD) and the function generator together with the centre‐zero milliammeter costs another Rs. 6000/‐ (about 180 USD). Where uninterrupted power supply is a problem, an inverter and a 12‐volt battery together costing about RS. 5000/‐ (about 150 USD) would be required". The study authors did not report adverse events, or acceptability of treatment. See summary of findings Table 8.
Low‐level laser therapy compared to simple dressing
One study with 25 participants (Barreto 2010), evaluated the effect of low‐level laser therapy compared to simple dressing on ulcer size after 12 weeks (primary outcome ‐ healing of ulcer). As with regards to the ulcer size, the results were inconclusive (MD ‐0.60 cm², 95% CI ‐6.47 to 5.27; Analysis 11.1). The study also reports the differences in ulcer depth (MD ‐1.30 mm, 95% CI ‐5.26 to 2.66; Analysis 11.2).
We judged the evidence to be of very low certainty and have very little confidence in the effect estimates. We downgraded due to study limitations (unclear allocation concealment, no blinding of outcome assessor), and due to indirectness (we are unsure if the intervention ‐ laser therapy ‐ is available to people with ulcers caused by nerve damage in leprosy) and due to imprecision (1 study, small sample size, wide CI). The study authors reported costs (secondary outcome). Costs were not analysed between groups, but the trial authors state: "Patients have an average of 3.4 simple dressings per week at the dressing service of UREMC, resulting in an estimated expenditure of USD 100,000 per year on disposable dressing material alone." The study authors did not report adverse events or acceptability of treatment. See summary of findings Table 9.
Intralesional pentoxifylline compared to daily simple dressing
One study with 40 participants evaluated the effect of intralesional pentoxifylline (injection) compared to daily simple dressing on healing of ulcer(s) (primary outcome) (Mikhael 2015). The authors found a risk ratio (RR) of 5.00 (95% CI 1.25 to 19.99) for healing of ulcers at eight weeks (Analysis 12.1). They also found a MD in ulcer depth of ‐0.22 cm (95% CI ‐0.40 to ‐0.04, Analysis 12.2). We judged the evidence to be of very low certainty and have very little confidence in the effect estimates presented. We downgraded due to study limitations (unclear allocation concealment and unclear if there was blinding of outcome assessor) and due to imprecision (1 small study, very wide CIs). The participants were asked about possible side effects. The only adverse events (secondary outcome) reported was tolerable pain during the injection (very low‐certainty evidence). We downgraded due to study limitations mentioned and in addition it was unclear how information of side effects was documented and if both intervention and control group were asked. The study authors did not report acceptability of treatment or costs. See summary of findings Table 10.
Light‐emitting diode (LED) compared to conventional dressing therapy
One study with 60 participants evaluated the effect of light‐emitting diode (LED, infrared or long visible wavelength light) compared to conventional dressing therapy on mean change of wound size (primary outcome ‐ healing of ulcer) (Lee 2012). The study authors reported that the average reduction in wound size was 26.55 mm3/day in the control group and 338.02 mm3/day in the LED group (MD 311.47, 95% CI 106.47 to 516.47; Analysis 13.1). The research period was eight months, but the exact length of follow‐up was not reported. We judged the evidence to be of very low certainty and have very little confidence in the effect estimates. We downgraded due to study limitations (concealment or sequence generation not reported, no blinding) and due to imprecision (only 1 study, few participants, wide CI). The study authors did not report on adverse events, or on acceptability of treatment or costs. See summary of findings Table 11.
Topical human amniotic membrane‐mesenchymal stem cell‐conditioned medium gel alone, with vitamin C or with vitamin E
One study with 66 participants and three arms evaluated the effect of topical human amniotic membrane‐mesenchymal stem cell‐conditioned medium (hAMMSC‐CM) and a mixture of topical hAMMSC‐CM + vitamin C and hAMMSC‐CM + vitamin E on healing of ulcer (primary outcome) (Prakoeswa 2018). The three arms, with 22 participants each, evaluated hAMMSC‐CM + vitamin C versus hAMMSC‐CM , hAMMSC‐CM + vitamin E versus hAMMSC‐CM and hAMMSC‐CM + vitamin C versus a mixture of topical hAMMSC‐CM + vitamin E. When comparing hAMMSC‐CM + vitamin C versus hAMMSC‐CM the authors found a mean difference (MD) at eight weeks follow‐up in ulcer size of 0.31 cm² (95% CI ‐0.35 to 0.97, Analysis 14.1) and ulcer depth of ‐0.10 cm² (95% CI ‐0.17 to ‐0.03, Analysis 14.2). For hAMMSC‐CM + vitamin E versus hAMMSC‐CM the MD in ulcer size was 1.14 cm² (95% CI 0.32 to 1.96, Analysis 15.1) and ulcer depth was ‐0.08 cm² (95% CI ‐0.17 to 0.01, Analysis 15.2). Finally, when comparing hAMMSC‐CM + vitamin C versus a mixture of topical hAMMSC‐CM + vitamin E, the MD in ulcer size was 0.83 cm² (95% CI ‐0.03 to 1.69, Analysis 16.1) and ulcer depth was 0.02 cm² (95% CI ‐0.06 to 0.10, Analysis 16.2). Overall there was little or no difference between the treatment groups.
We judged the evidence to be of very low certainty and have very little confidence in the effect estimates presented. We downgraded due to study limitations (unclear concealment of allocation, unclear if there was blinding of outcome assessor, clinician or patient) sparse data and imprecision (only 1 study, few participants). The study authors reported that no adverse events (such as allergy or infection) were encountered in any group. The study authors did not report acceptability of treatment or costs. See summary of findings Table 13; summary of findings Table 14; summary of findings Table 15.
Interventions for people with leprosy and no existing ulcer(s)
Wax therapy compared to foot soaks
One study, with a total of 44 participants, evaluated the effect of wax therapy compared to foot soaks, and the authors reported that the participants who were in the group that were given wax therapy felt subjectively much better than those who had foot soaks (acceptability of treatment ‐ secondary outcome) (Sharma 2005). The study also measured the skin being fissure and callous‐free (tertiary outcome) and results were in favour of wax therapy at six weeks (RR 2.22, 95% CI 1.07 to 4.60; Analysis 17.1). However, we judged this evidence to be of very low certainty and have very little confidence in this evidence. We downgraded the evidence for the results of these two outcomes due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded, and study authors are not clear in numbers of persons or feet reported), and due to imprecision (1 study with 44 participants, wide CI) and due to indirectness (wax therapy probably not available to most people with leprosy as treatment is given in hospital). Adverse events and cost of intervention were not reported. See summary of findings Table 12.
Discussion
Summary of main results
It is not possible to draw any firm conclusions based on the available evidence, which was of very low certainty.
We have presented results for our primary outcomes, measured by the following key comparisons.
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Zinc tape compared to magnesium sulphate glycerine (summary of findings Table for the main comparison).
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Zinc tape compared to povidone iodine (10%) (summary of findings Table 2).
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Adhesive zinc tape compared to gauze soaked in Eusol (summary of findings Table 3).
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Topical phenytoin compared to saline dressing (summary of findings Table 5).
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Footwear ‐ canvas shoes compared to PVC boots (summary of findings Table 6).
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Exposure to pulsed magnetic fields (plus self‐care and protective footwear) compared to self‐care and footwear (summary of findings Table 8).
Only one of the trials measured our primary outcome 'prevention of ulcers(s)': the study compared canvas shoes with PVC boots, and none of the participants developed new ulcers during the duration of the trial (1 year). Seventy‐two participants had scars (not ulcers) at the start of the study (27 in the canvas group and 45 in the PVC group). Although, it is worth noting that some treatments are not intended to prevent ulcers.
Healing of existing ulcers was measured by all of the key comparisons, as follows.
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There were more healed ulcers and a greater reduction in mean ulcer area in the zinc tape group compared to the magnesium sulphate glycerine group.
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Although there was a bigger reduction in mean ulcer area with zinc tape, there was no clear difference between zinc tape and povidone iodine.
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The healing time for deep ulcers in the zinc tape group was 17 days compared to 30 days in a group whose ulcers were treated with gauze soaked in Eusol.
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Two studies suggested that topical phenytoin had a better effect on healing of ulcers compared to saline dressing: a greater mean percentage reduction of ulcer area/volume with phenytoin.
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There was no clear difference in achieving healed ulcers or becoming ulcer‐free in those wearing canvas shoes compared to PVC boots.
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There was no clear difference in volume of ulcers between people exposed to pulsed magnetic fields (plus self‐care and protective footwear) versus those who practiced self‐care and wore protective footwear.
Half of the key comparisons measured and reported adverse events, either those sufficiently serious to stop the intervention, or minor ones reported by participants.
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There were no signs of skin sensitisation in either of the following groups: zinc tape or gauze soaked in Eusol.
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No adverse effects were observed in those treated with phenytoin or normal saline.
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Comparing canvas shoes with PVC boots, the only issue reported was that the PVC boots could become very hot in strong sunlight, leading to the possibility of burnt feet.
Some key treatment categories, such as self‐care programmes, education, information, dry dressings, or skin care were not assessed by any included study, but in some studies, they may have been added to the intervention or used in the control groups. None of the 14 included studies measured quality of life. Only one study measured our tertiary outcome, 'prevention or treatment of other skin changes, such as cracking, thickening or pigmentary changes'.
Overall completeness and applicability of evidence
The findings of this review did not allow us to fully address our objectives; we are restrained by the limited types of interventions assessed, the included studies not reporting our outcomes of interest (apart from healing of ulcers), and the general low certainty of the evidence we could include.
Many of the included studies assessed novel interventions in single small trials, which were not sufficiently powered to provide meaningful, reliable results. However, the studies were based in the Americas, Africa, and Asia, and thus involved the community of people affected by leprosy. In general, the follow‐up time for the outcome, 'healing of existing ulcers' was adequate.
A number of important interventions were not assessed by the included studies. These included self‐care programmes, education, information, dry dressings, or skin care; however, in some studies, they may have been added to the intervention or used in the control groups.
Only one study measured prevention of ulcer(s) and prevention or treatment of other skin changes; however, healing of existing ulcer(s) was very well measured. Adverse events were mentioned in some studies, but it was often unclear how this outcome was measured. None of the studies reported any quality of life measures. The acceptability of treatment was reported in a few studies, but we generally lack information on how this outcome was measured. A few studies reported the direct cost involved.
Certainty of the evidence
There are 15 different comparisons presented in our 'Summary of findings' table, and the body of evidence for each comparison is very limited for each intervention. In our GRADE outcomes, we downgraded each outcome by at least one level for study limitations, mainly in relation to potential selection, detection, performance, or attrition bias. We downgraded all outcomes but one (acceptability of treatment in summary of findings Table 6) for imprecision due to single study data with only a small number of participants analysed. This meant that the 95% CIs surrounding any estimated effect sizes were wide, showing great uncertainty with the evidence provided. Indirectness was also a reason for downgrading in six comparisons: topical ketanserin (2%) compared to clioquinol cream (3%) or zinc paste (summary of findings Table 4), footwear ‐ canvas shoes compared to PVC boots (summary of findings Table 6), padded moulded double‐rocker plaster shoe compared to padded below‐knee plaster (summary of findings Table 7), low‐level laser therapy compared to simple dressing (summary of findings Table 9), intralesional pentoxifylline compared to daily simple dressing (summary of findings Table 10), and wax therapy compared to foot soaks (summary of findings Table 12). Hence, we rated all outcomes as very low certainty, except for acceptability of treatment which we rated as moderate in the comparison of footwear ‐ canvas shoes compared to PVC boots for ulceration and other skin changes caused by nerve damage in leprosy (summary of findings Table 6).
Potential biases in the review process
The search for literature in the various databases is finite, until our search dates, so newer studies might be missing. We identified two ongoing studies. Two review authors independently selected studies for inclusion, extracted data, and assessed risk of bias with a third review author acting as arbiter in order to minimise the risk of bias in the review process. In addition, we attempted to contact a few study authors for additional information. None of the review authors had a conflict of interest regarding any of the interventions in this review.
A few studies included participants that had several treated ulcers, and thus an element of clustering. This should have been accounted for in the analysis. In the studies that explicitly included people with several ulcers without reporting how this was handled in the analysis, we made a note of this in the Characteristics of included studies tables. However, we judged that the clustering was not comprehensive enough to make any difference to the reported results.
For this version of the review, we did not search for unpublished and ongoing trials by corresponding with authors; field experts; and experts on tropical medicine or leprosy or both. Thus, there might be a risk we may not have included all the evidence available.
We judged that the clinical heterogeneity between trials was so big that we did not pool any results.
Agreements and disagreements with other studies or reviews
The evidence base is very limited for interventions for ulceration and other skin changes caused by nerve damage in leprosy. As stated in a comment in Srinivasan 1989, lots of interventions have been tried for healing such ulcers and he warned against novel "healing agents". Our review identified many interventions that had been tried out in single trials, hardly any replicated by others. We have not identified other reviews that address interventions for prevention or healing of ulcers and other skin changes in leprosy.
Examples of ulcers in patients with leprosy: (A) Blister formed after walking long distances that later became an ulcer. (B) Fissure on the base of the second toe of the right foot. (C) Right medial malleolus ulcer from a patient with leprosy and HBP. (D) Plantar ulcer on the region of second metatarsal head. (E) Myiasis in a chronic leg ulcer. (F) Chronic ulcer on a lower limb stump.
Pictures first appeared in Barreto 2010, with kind permission from Josafá Gonçalves Barreto.
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
Study flow diagram.
Comparison 1 Zinc tape versus magnesium sulphate/glycerin, Outcome 1 Number of ulcers healed after one month.
Comparison 1 Zinc tape versus magnesium sulphate/glycerin, Outcome 2 Mean ulcer area (mm2) after one month.
Comparison 2 Zinc tape versus povidone iodine (10%), Outcome 1 Mean reduction of ulcer area at six weeks (mm2).
Comparison 3 Topical ketanserin (2%) versus clioquinol cream (3%) or zinc paste, Outcome 1 Healing of ulcer after three months.
Comparison 4 Topical phenytoin (unknown solution) versus saline dressing, Outcome 1 Mean percentage of ulcer volume reduction at four weeks.
Comparison 5 Topical 2% phenytoin versus saline dressing, Outcome 1 Mean percentage reduction of ulcer size area at four weeks.
Comparison 6 Topical 4% phenytoin versus saline dressing, Outcome 1 Mean percentage reduction of ulcer area at four weeks.
Comparison 7 Topical 4% phenytoin versus 2% phenytoin, Outcome 1 Mean percentage reduction of ulcer size at four weeks.
Comparison 8 Footwear ‐ canvas shoes versus PVC boots, Outcome 1 Number of persons with healed ulcers at one year.
Comparison 8 Footwear ‐ canvas shoes versus PVC boots, Outcome 2 Number of persons having ulcers not healed at one year.
Comparison 9 Padded moulded double‐rocker plaster shoe versus padded below‐knee plaster, Outcome 1 Ulcers fully or nearly healed at six weeks.
Comparison 10 Exposure to pulsed magnetic fields (in addition to self‐care and protective footwear) versus self‐care and footwear, Outcome 1 Mean volume (cm³) of ulcers at four to five weeks.
Comparison 11 Low‐level laser therapy versus simple dressing, Outcome 1 Size of ulcer (area, cm²) after 12 weeks.
Comparison 11 Low‐level laser therapy versus simple dressing, Outcome 2 Size of ulcer (depth, mm) after 12 weeks.
Comparison 12 Intralesional pentoxifylline versus daily simple dressing, Outcome 1 Complete healing of ulcer at 8 weeks.
Comparison 12 Intralesional pentoxifylline versus daily simple dressing, Outcome 2 Ulcer depth (cm) at 8 weeks.
Comparison 13 Light‐emitting diode (LED) versus conventional dressing, Outcome 1 Mean reduction in wound size (mm³) at 8 months.
Comparison 14 hAMMSC‐CM + vitamin C versus hAMMSC‐CM, Outcome 1 Mean reduction (cm2) in ulcer size at eight weeks.
Comparison 14 hAMMSC‐CM + vitamin C versus hAMMSC‐CM, Outcome 2 Mean reduction (cm2) in ulcer depth at eight weeks.
Comparison 15 hAMMSC‐CM + vitamin E versus hAMMSC‐CM, Outcome 1 Mean reduction (cm2) in ulcer size at eight weeks.
Comparison 15 hAMMSC‐CM + vitamin E versus hAMMSC‐CM, Outcome 2 Mean reduction (cm2) in ulcer depth at eight weeks.
Comparison 16 hAMMSC‐CM + vitamin E versus hAMMSC‐CM + vitamin C, Outcome 1 Mean reduction (cm2) in ulcer size at eight weeks.
Comparison 16 hAMMSC‐CM + vitamin E versus hAMMSC‐CM + vitamin C, Outcome 2 Mean reduction (cm2) in ulcer depth at eight weeks.
Comparison 17 Wax therapy versus foot soaks, Outcome 1 Number of feet being fissure‐ and callous‐free at six weeks.
| Zinc tape compared to magnesium sulphate glycerin for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with magnesium sulphate/glycerin | Risk with Zinc tape | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (number of ulcers healed after 1 month) | Study population | RR 2.00 | 28 | ⊕⊝⊝⊝ | ‐ | |
| 143 per 1000 | 286 per 1000 | |||||
| Primary outcome: healing of ulcers (mean ulcer area (mm3) | The mean ulcer area was 56.7 | MD 14.3 lower | ‐ | 28 | ⊕⊝⊝⊝ | ‐ |
| Priimary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: costs | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (such as 35% lost to follow‐up, consecutive cases were randomly allocated, no blinding of outcome assessor, and potential unit of analysis error). Also downgraded two levels for imprecision due to sparse data and wide confidence intervals. | ||||||
| Zinc tape compared to povidone iodine (10%) for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with povidone iodine (10%) | Risk with zinc tape | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (mean reduction of ulcer area at 6 weeks (mm2)) | The mean reduction of ulcer area at six weeks was 260 | MD 128 higher | ‐ | 38 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: costs | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (quasi‐randomised trial, high loss to follow‐up, and no reporting of blinding of outcome assessor), and two levels due to imprecision (1 study, few participants, wide confidence interval). | ||||||
| Adhesive zinc tape compared to gauze soaked in eusol for ulceration caused by nerve damage in leprosy | |||||
| Patient or population: ulceration caused by nerve damage in leprosy | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
| Risk with gauze soaked in eusol | Risk with adhesive zinc tape | ||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (days) | Total number of participants was 90 and they had a total of 128 plantar ulcersb. The average healing time was shorter for the group treated with zinc tape. The results varied between the two hospitals involved. In one hospital, it took about 20 days (CI 18 to 23) for superficial ulcers to heal in the zinc tape group versus about 30 (CI 27 to 33) in the gauze group. For deep ulcers the average healing time was two weeks more. In the other hospital, the average number of days to heal in the zinc tape group for superficial wounds was about 13 (CI 9 to 15) days and 23 (CI 16 to 28) days in the gauze group. For deep ulcers it took 17 days (CI 12 to 20) in the zinc tape group and 30 (CI 21 to 63) in the gauze group. | ‐ | 90 | ⊕⊝⊝⊝ | |
| Primary outcome: adverse events (skin sensitisation at 2 months) | The study authors reported: "No signs of skin sensitization were observed in either the tape‐treated or the gauze‐treated wounds". | ‐ | 90 (1 RCT) | ⊕⊝⊝⊝ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | Not clear how or if this was adequately measured. However, the study authors say: "The zinc tape has the following advantages: 1. shorter healing time, 2. low cost, 3. easy application, 4. more convenient for patients: (a) can be worn under shoes without causing pressure; (b) socially more acceptable, no bandages are needed". | ‐ | 90 (1 RCT) | ⊕⊝⊝⊝ | |
| Secondary outcome: costs | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | |||||
| GRADE Working Group grades of evidence | |||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (allocation random alternate basis, no blinding outcome assessor, and inadequate reporting of data), and two levels for imprecision (few participants)). | |||||
| Topical ketanserin (2%) compared to clioquinol cream (3%) or zinc paste for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with clioquinol cream (3%) or zinc paste | Risk with topical ketanserin (2%) | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (healing of ulcer at 3 months) | Study population | RR 6.00 | 66 | ⊕⊝⊝⊝ | ‐ | |
| 61 per 1000 | 364 per 1000 | |||||
| Primary outcome: adverse events | Treatment was not suspended in any of the patients because of side effects | ‐ | 66 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (randomisation procedure not reported, blinding not reported, and unclear if appropriate statistical analysis used) and two levels due to imprecision (1 study, very wide confidence interval). | ||||||
| Topical phenytoin compared to saline dressing for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with saline dressing | Risk with topical phenytoin (2%) | |||||
| Primary outcome: prevention of ulcers | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcers (mean percentage of ulcer volume reduction at 4 weeks (Bansal 1993)) | The mean percentage reduction of ulcer volume was 55.5% | MD 16.60% higher | ‐ | 100 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcers (mean percentage reduction of ulcer size area at 4 weeks (Bhatia 2004)) | The mean percentage reduction of ulcer size area was 49.1% | MD 39.30% higher | 23 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Primary outcome: adverse events (up to 4 weeks) | No adverse effects were observed in any of the patients treated with phenytoin or normal saline. | ‐ | 123 (2 RCTs) | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (non‐adequate random sequence generation, unit of analysis error) and two levels due to imprecision (sparse data and consequently wide confidence interval). | ||||||
| Footwear ‐ canvas shoes compared to PVC boots for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with PVC boots | Risk with canvas shoes | |||||
| Primary outcome: prevention of ulcer (number of persons developing new ulcers at 1 year) | None of the 45 participants with scars developed new ulcers | None of the 27 participants with scars developed new ulcers | ‐ | 72 (1 RCT) | ⊕⊝⊝⊝ | Seventy‐two participants had scars (not ulcers) at the start of the study (27 in canvas group, 45 in PVC group) and none of these developed new ulcers during the year. |
| Primary outcome: healing of ulcer (number of persons being ulcer‐free at 1 year) | Study population | RR 1.16 | 38 | ⊕⊝⊝⊝ | ‐ | |
| 692 per 1000 | 803 per 1000 | |||||
| Primary outcome: healing of ulcer (number of persons having ulcers not healed at 1 year) | Study population | RR 0.52 | 38 | ⊕⊝⊝⊝ | ‐ | |
| 308 per 1000 | 160 per 1000 | |||||
| Primary outcome: adverse events | One adverse comment was that PVC boots could become very hot in strong sunlight, with possibility of burning the feet | ‐ | 38 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | The canvas shoes were socially acceptable, but 85% of farmers rated them as good for their work, rather than "excellent" (8%) at first follow‐up at three months. More than 80% rated the PVC boots as excellent for social acceptability and work suitability. | ‐ | 110d (1 RCT) | ⊕⊕⊕⊝ | ‐ | |
| Secondary outcome: costs | See comment | ‐ | 110d (1 RCT) | ‐ | Costs not reported. Study authors only reported that canvas shoes and PVC boots cost the same. PVC boots are more durable than canvas shoes. | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. Two levels due to study limitations (unclear randomisation, unclear blinding) and two levels due to imprecision (1 study, small number of participants, wide confidence interval). | ||||||
| Padded moulded double‐rocker plaster shoe compared to padded below‐knee plaster for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with padded below‐knee plaster | Risk with padded moulded double‐rocker plaster shoe | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (ulcers fully or nearly healed at 6 weeks) | Study population | RR 0.96 | 55 | ⊕⊝⊝⊝ | ‐ | |
| 875 per 1000 | 840 per 1000 | |||||
| Primary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | Study authors stated: "The MD shoe is more acceptable to the patient" | ‐ | 55 | ⊕⊝⊝⊝ | ‐ | |
| Secondary outcome: costs of intervention | Study authors stated: "The MD shoe is ......cheaper to apply and, more important.." | ‐ | 55 | ⊕⊝⊝⊝ | ‐ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| a Downgraded by four levels to very low‐certainty evidence. Two levels due to study limitations (no information on baseline characteristics; unit of analysis is ulcers, not patients; unclear randomisation procedure; unclear if blinding of outcome assessor), one level due to indirectness (padded moulded double‐rocker plaster shoe and padded below‐knee plasters might not be acceptable interventions today for people with leprosy), and one level due to imprecision (1 study, small number of participants). | ||||||
| Exposure to pulsed magnetic fields (in addition to self‐care and protective footwear) compared to self‐care and footwear for ulceration and other skin changes caused by nerve damage in leprosy | |||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | |||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | |
| Risk with self‐care and footwear | Risk with exposure to pulsed magnetic fields (in addition to self‐care and protective footwear) | ||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (at 4 to 5 weeks) | In the control group, the geometric mean volumes of the ulcers were 2843 cu mm and 1478 cu mm on the day of admission and at the end of treatment (P = 0.03); the corresponding values in the PMF group were 2428 cu mm and 337 cu mm, respectively (P < 0.001). A decrease in the volume of 40% or more was observed in 53% of control patients and 89% of PMF participants (P = 0.02): a decrease of 80% or more was observed in none of the controls and in 33% of PMF participants. | ‐ | 33 (1 RCT) | ⊕⊝⊝⊝ | |
| Primary outcome 2 (healing of ulcer): Mean volume of ulcers at four to five weeks | The mean volume (cm2) after four to five weeks was 1.48 | MD was 1.14 lower (5.37 lower to 3.09 higher) | ‐ | 33 (1 RCT) | ⊕⊝⊝⊝ |
| Primary outcome 3 (adverse events) | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome 1 (quality of life) | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome 2 (acceptability of treatment) | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome 3 (cost of intervention) | The authors state: "The cost of construction of an enclosure is around Rs. 5000/‐ (about 150 USD) and the function generator together with the centre‐zero milliammeter costs another Rs. 6000/‐ (about 180 USD). Where uninterrupted power supply is a problem, an inverter and a 12‐volt battery together costing about RS. 5000/‐ (about 150 USD) would be required." | ‐ | 33 (1 RCT) | ⊕⊝⊝⊝ | |
| *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). | |||||
| GRADE Working Group grades of evidence | |||||
| a Downgraded by three levels. One level due to study limitations (unclear randomisation procedure, 7 of 20 patients lost to follow‐up) and two levels due to imprecision (1 study with few participants). | |||||
| Low‐level laser therapy compared to simple dressing for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with simple dressing | Risk with low‐level laser therapy | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (size of ulcer (area) at 12 weeks (cm2)) | The mean size of ulcer (area) after 12 weeks was 4.4 | MD 0.60 lower | ‐ | 23 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcer (size of ulcer (depth) at 12 weeks (mm)) | The mean size of ulcer (depth) after 12 weeks was 5.4 | MD 1.30 mm lower | ‐ | 23 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse effects | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: costs | Costs not analysed between groups, but trial authors state: "Patients have an average of 3.4 simple dressings per week at the dressing service of UREMC, resulting in an estimated expenditure of USD 100,000 per year on disposable dressing material alone." | ‐ | 23 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels. One level due to study limitations (unclear allocation concealment, no blinding of outcome assessor), one level due to indirectness (we are unsure if the intervention ‐ laser therapy ‐ is available to people with ulcers caused by nerve damage in leprosy) and two levels due to imprecision (1 study, small sample size, wide confidence interval). | ||||||
| Intralesional pentoxifylline compared to daily simple dressing for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with daily simple dressing | Risk with intralesional pentoxifylline | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (complete healing of ulcer at 4 weeks) | Study population | OR 9.00 | 40 | ⊕⊝⊝⊝ | ‐ | |
| 100 per 1000 | 500 per 1000 | |||||
| Primary outcome: healing of ulcer (ulcer depth (cm) at 4 weeks) | The mean ulcer depth was 0.45 | MD 0.22 cm lower | ‐ | 40 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events (at 4 weeks) | The patients were asked about any possible side effects such as pain, skin rash, discolouration, or discomfort. There were no side effects, except tolerable pain during the injection in intervention group. | ‐ | 40 | ⊕⊝⊝ | ‐ | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment and unclear if there was blinding of outcome assessor) and two levels due to imprecision (1 small study, very wide confidence intervals). | ||||||
| Light‐emitting diode (LED) irradiation compared to conventional dressing therapy for ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration and other skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with conventional dressing therapy | Risk with LED irradiation | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: healing of ulcer (mean change of wound size (mm3) after 8 months treatment) | The mean change of wound size was 26.55 | MD 311.47 higher | ‐ | 60 | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (concealment or sequence generation not reported, no blinding) and two levels due to imprecision (only 1 study, few participants, wide confidence interval). | ||||||
| Wax therapy compared to foot soaks for skin changes caused by nerve damage in leprosy | ||||||
| Patient or population: skin changes caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with foot soaks | Risk with wax therapy | |||||
| Primary outcome: healing of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Tertiary outcome: prevention and treatment of other skin changes (number of feet being fissure‐ and callous‐free at 6 weeks) | Study population | RR 2.22 | 44 | ⊕⊝⊝⊝ | ‐ | |
| 300 per 1000 | 666 per 1000 | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Primary outcome: adverse effects | ‐ | ‐ | ‐ | ‐ | Not reported | |
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | Not reported | |
| Secondary outcome: acceptability of treatment (at 6 weeks) | "Patients given wax therapy felt subjectively much better than those who had foot soaks" | ‐ | 44 | ⊕⊝⊝⊝ | ‐ | |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by four levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded, and study authors are not clear in numbers of persons or feet reported), two levels due to imprecision (1 study with 44 participants, wide confidence interval) and one level due to indirectness (wax therapy probably not available to most people with leprosy; treatment is given in hospital). | ||||||
| hAMMSC‐CM + vitamin C compared to hAMMSC‐CM for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with hAMMSC‐CM | Risk with hAMMSC‐CM + vitamin C | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Primary outcome: healing of ulcer (size, cm², at 8 weeks) | The mean reduction was 1.70 | MD 0.31 cm2 higher (0.35 lower to 0.97 higher) | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Primary outcome: healing of ulcer (depth, cm², at 8 weeks) | The mean reduction was 0.35 | MD 0.10 cm2 lower (0.17 lower to 0.03 lower) | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | |
| Primary outcome: adverse events | "No adverse events were encountered in any group" | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | ||
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | Not reported | |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded), two levels due to imprecision (1 study with a total of 66 patients with three arms). | ||||||
| hAMMSC‐CM + vitamin E compared to hAMMSC‐CM for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with hAMMSC‐CM | Risk with hAMMSC‐CM + vitamin E | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Primary outcome: healing of ulcer (size, cm2 at 8 weeks) | The mean reduction was 1.70 | MD 1.14 cm2 higher (0.35 higher to 0.97 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcer (depth, cm2 at 8 weeks) | The mean reduction was 0.35 | MD 0.08 cm2 lower (0.17 lower to 0.01 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | Study authors reported: "No adverse events were encountered in any group" | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ | ||
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded), two levels due to imprecision (1 study with a total of 66 patients with 3 arms). | ||||||
| hAMMSC‐ CM +vitamin E compared to hAMMSC‐CM + vitamin C for ulceration caused by nerve damage in leprosy | ||||||
| Patient or population: ulceration caused by nerve damage in leprosy | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with hAMMSC‐CM + vitamin C | Risk with hAMMSC‐CM + vitamin E | |||||
| Primary outcome: prevention of ulcer | ‐ | ‐ | ‐ | ‐ | ‐ | Not applicable |
| Primary outcome: healing of ulcer (size, cm2, at 8 weeks) | The mean reduction was 2.01 | MD 0.83 cm2 higher (0.03 lower to 1.69 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: healing of ulcer (depth, cm2, at 8 weeks) | The mean reduction was 0.25 | MD 0.02 cm2 higher (0.06 lower to 0.10 higher) | ‐ | 44 (1 RCT) | ⊕⊝⊝⊝ | ‐ |
| Primary outcome: adverse events | Study authors reported: "No adverse events were encountered in any group" | 44 (1 RCT) | ⊕⊝⊝⊝ Very lowb | ‐ | ||
| Secondary outcome: quality of life | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outcome: acceptability of treatment | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| Secondary outome: cost of intervention | ‐ | ‐ | ‐ | ‐ | ‐ | Not reported |
| *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). | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded by three levels to very low‐certainty evidence. One level due to study limitations (unclear allocation concealment, unclear if outcome assessor was blinded), two levels due to imprecision (1 study with a total of 66 patients with three arms). | ||||||
| Term | Definition |
| Afferent nerves | Sensory nerves that carry information from the outside world, such as sensations of heat, cold, and pain, to the brain and spinal cord. |
| Autonomic fibres | Nerve fibres that collectively make up the sympathetic (involuntary) and parasympathetic ('relaxation response') parts of the autonomic peripheral nervous system. Common symptoms of autonomic nerve damage include an inability to sweat normally and change in vasodilatation. |
| Bacilli | Plural of bacillus, bacteria. |
| Capillary haemodynamics | Blood flow in the capillaries, where oxygen transfer occurs in the body. |
| Efferent nerves | Motor nerves that transmit impulses from the brain and spinal cord to the muscles. |
| Facial nerve | It is composed of motor, sensory fibres and autonomic fibres. The important motor part innervates the facial muscles responsible for eye closure and mouth and facial movements. In leprosy, the eye is at risk of corneal ulceration for exposure and decreased lachrymal gland function. |
| Fibroblast | A large flat cell that secretes the proteins that form collagen and elastic fibres and the substance between the cells of connective tissue. |
| Medial nerve | It is composed of motor, sensory, and autonomic fibres. The autonomic fibres are responsible for sweating and oil gland secretion. Sensation is affected on the lateral side of the forearm and the palmar side of the hand, thumb, index, middle, and half of the ring finger. It innervates the muscles of the hand and in leprosy affects predominately the intrinsic muscles of the thumb, making opposition and prehension difficult. Weakness and paralysis causes the thumb to be flat within the hand. |
| Motor fibres | Motor nerves (or efferent nerves), transmit impulses from the brain and spinal cord to the muscles. |
| Multibacillary | Having numerous bacilli. "Multibacillary leprosy" classification by World Health Organization for the purpose of treatment is a person with more than five lesions. |
| Paucibacillary | Having just a few bacilli. "Paucibacillary leprosy" classification by World Health Organization for the purpose of treatment is a person with five or fewer lesions. |
| Peripheral nerve | A vast transmission network of afferent and efferent nerves from the central nervous system (brain and spinal cord) distally to every other part of the body. The motor, sensory, and autonomic fibres have specific functions within the area innervated by the specific peripheral nerve. Nerves can be composed primarily of motor or sensory fibres or be mixed, having both motor and sensory fibres. |
| Peroneal nerve | The common peroneal divides into the superficial and deep peroneal branches. The deep branch innervates the muscles of the anterior compartment of the leg (anterior tibial muscle, the long extensor muscle of the big toe and the long extensor muscles of the toes). When weak or paralysed, it makes it difficult to lift the foot and toes as well as evert the foot when walking. In leprosy, it is frequently referred to as "foot drop". Its sensory fibres innervate the lateral dorsal surface of the lower leg and foot. The sensory fibres of the superficial branch provides sensation to the web space of the big toe and the medial surface of the second toe. |
| Tibial nerve | One of the two major divisions of the sciatic nerve, it courses down the back of the leg to terminate as the medial and lateral plantar nerves in the foot; it supplies the hamstring muscles, the muscles of the back of the lower leg, and the intrinsic muscles of the foot. It causes clawing of the toes if muscles are paralysed. It provides sensation to the back of the leg and sole of the foot. The sensory loss to the sole of the foot puts the foot at high risk for injury and ulceration. |
| Sensory fibres | Sensory nerves (or afferent nerves), carry information from the outside world, such as sensations of temperature (hot, cold), touch, texture and pain, to the brain and spinal cord. They alert the body to pleasant feelings as well as to danger. |
| Sural nerve | A sensory nerve in the calf region (sura) of the leg. It is made up of collateral branches of the tibial nerve and common fibular nerve. |
| Trigeminal nerve | The three‐branch trigeminal (fifth cranial) nerve innervating the face, eyes, nose, mouth, and jaws. The corneal sensory loss in leprosy can cause the eye to be at risk for increased dryness and corneal abrasions. |
| Ulceration | Formation or development of an ulcer. On the skin, it is a loss of epidermis, often part of the dermis and even subcutaneous fat layers of the skin. |
| Ulnar nerve in the upper extremity | It is composed of motor, sensory, and autonomic fibres. The autonomic fibres are responsible for sweating and oil gland secretion. Sensation is affected on the ulnar (medial) side of the forearm, hand, the palmar side of the 5th and half of the 4th fingers. It innervates the muscles of the hand and in leprosy affects predominately the distal intrinsic muscles used for fine motor tasks. Weakness and paralysis causes finger clawing. |
| Vasodilation | A widening of the blood vessels caused by a relaxation of the smooth muscle cells in the vessel wall. The sympathetic nervous system has nerves that play an important role in vasodilatation and vasoconstriction. |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Number of ulcers healed after one month Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Mean ulcer area (mm2) after one month Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction of ulcer area at six weeks (mm2) Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Healing of ulcer after three months Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage of ulcer volume reduction at four weeks Show forest plot | 1 | 100 | Mean Difference (IV, Random, 95% CI) | 16.60 [8.46, 24.74] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage reduction of ulcer size area at four weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage reduction of ulcer area at four weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean percentage reduction of ulcer size at four weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Number of persons with healed ulcers at one year Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Number of persons having ulcers not healed at one year Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Ulcers fully or nearly healed at six weeks Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean volume (cm³) of ulcers at four to five weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Size of ulcer (area, cm²) after 12 weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| 2 Size of ulcer (depth, mm) after 12 weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Complete healing of ulcer at 8 weeks Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
| 2 Ulcer depth (cm) at 8 weeks Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction in wound size (mm³) at 8 months Show forest plot | 1 | Mean Difference (IV, Random, 95% CI) | Totals not selected | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction (cm2) in ulcer size at eight weeks Show forest plot | 1 | 44 | Mean Difference (IV, Random, 95% CI) | 0.31 [‐0.35, 0.97] |
| 2 Mean reduction (cm2) in ulcer depth at eight weeks Show forest plot | 1 | 44 | Mean Difference (IV, Random, 95% CI) | ‐0.10 [‐0.17, ‐0.03] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction (cm2) in ulcer size at eight weeks Show forest plot | 1 | 44 | Mean Difference (IV, Fixed, 95% CI) | 1.14 [0.32, 1.96] |
| 2 Mean reduction (cm2) in ulcer depth at eight weeks Show forest plot | 1 | 44 | Mean Difference (IV, Random, 95% CI) | ‐0.08 [‐0.17, 0.01] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mean reduction (cm2) in ulcer size at eight weeks Show forest plot | 1 | 44 | Mean Difference (IV, Random, 95% CI) | 0.83 [‐0.03, 1.69] |
| 2 Mean reduction (cm2) in ulcer depth at eight weeks Show forest plot | 1 | 44 | Mean Difference (IV, Random, 95% CI) | 0.02 [‐0.06, 0.10] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Number of feet being fissure‐ and callous‐free at six weeks Show forest plot | 1 | Risk Ratio (M‐H, Random, 95% CI) | Totals not selected | |
