We have included a glossary with an explanation of some of the terms we have used, see Table 1.
|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, sometimes called 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 2002). Official figures show that almost 189,000 people, mainly in Asia and Africa, were affected at the beginning of 2013, with approximately 232,000 new cases reported during 2012, which is 6231 more cases than in 2011 (WHO 2013). The World Health Organization (WHO) stated in 2012 that less than 20 countries reported more than 1000 new cases, which indicates that leprosy is gradually becoming limited to a small number of countries (WHO 2012).
Although the incidence rate is declining slowly worldwide, it is rising in a few places. The proportion of children under 15 years of age among new cases of leprosy ranges widely in different countries: from 0.6% to 41.3% in 2012 (WHO 2012). Person-to-person transmission remains a problem; there are significant numbers of childhood cases, and many people suffer from the consequences of leprosy (McDougall 2002). Numbers are based on the people registered for treatment. Over 14,000 new cases of leprosy in 2012 were diagnosed with grade 2 disability (impairment of the eyes, hands, or feet), which is 0.25 per 100,000 population (WHO 2013), and in this report the proportion of new cases found with grade 2 disabilities ranged from 4.4% to 25.4%. This variation can be explained by the methods of detection and reporting in those countries: where there are low levels of grade 2 disabilities this indicates an increasing awareness of detecting cases early in communities and health systems. A total of 3427 relapses were reported from 105 countries in 2012 (WHO 2013).
South East Asia has the highest prevalence of leprosy, followed by the Americas, Africa, the Western Pacific, Eastern Mediterranean and Europe. Of all those identified as having the disease, 58% live in India, 16% live in Brazil, and 9% live in Indonesia (WHO 2012).
Chemotherapy with a combination of immunosuppressive and antibiotic drugs (multidrug therapy (MDT)) is used to treat leprosy (Lockwood 2002). The drugs used in MDT are rifampicin, dapsone, and clofazimine; they are effective in killing bacilli, but do not prevent further nerve damage. This nerve damage is caused by immune system responses, requiring other interventions such as corticosteroids, surgery, or both (Lockwood 2002). The effectiveness of corticosteroids has been evaluated in a systematic review (Van Veen 2007). Surgery for treating nerve damage in leprosy has been covered in another systematic review (Van Veen 2012). Virtually all people affected by leprosy and registered with their local health services are treated with MDT (WHO 2013). People affected by leprosy who are or have been treated with MDT are not infectious (WHO 2010).
Clinical manifestations and complications
Generally, leprosy starts with a patch or lesion on the skin, but it can also do damage to the nerves (Bell 1995; Lockwood 2002). Often the first signs are a lighter colour patch of skin with loss of hair, or sweating, or a loss of sensation to temperature and touch. If treated early, much of the nerve damage leading to problems in the face, hands, and feet can be prevented (Van Veen 2009). The principal manifestations are skin patches or lesions with a loss of sensation (flat or raised patches on the skin). Sometimes, there are only one or a few lesions, and sometimes there are numerous lesions, depending on host immunity. In those with a large number of bacteria, the skin may become diffusely thickened. Thickened skin; dry or cracked skin; or skin ulcers and peripheral neuropathy (inflammation of nerves) in the limbs damaging nerve function (autonomic, sensory, and motor fibres) may be later complications (Bell 1995; Lockwood 2002). Most complications are the result of nerve damage through direct invasion by the M. leprae bacteria or inflammation caused by reactions of the host's immune system.
Initially, the small sensory and autonomic nerve fibres in the skin are damaged, causing local loss of hair, sweating, and sensation and loss of the skin's ability to sweat. Damage to peripheral nerves eventually leads 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. 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 2002). If a new leprosy case is seen with a visible grade 2 disability (WHO 2013), then the diagnosis has been late. Community health education programs, health systems, or both, need to explore strategies to improve early case detection.
The primary peripheral nerves damaged by leprosy are the ulnar nerve in the arm, the peroneal and posterior tibial or sural nerves in the leg, and the trigeminal and facial nerves of the face. Major areas affected by nerve damage in leprosy are the hands (especially the palms), feet (especially the soles), and eyes (Lockwood 2002). The main complication of sensory nerve damage is ulceration followed by sensory loss, particularly of the feet (Lockwood 2002). 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 6 to 12 months (WHO 2006). However, even with treatment, some people with leprosy can have immune reactions during and after treatment, which 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 2002; 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. For those having permanent nerve damage, further damage and complications can be reduced by good self-care practices, the use of protective footwear, surgery, etc (Lockwood 2002). Existing guidelines (WHO 2011) emphasise the importance of preventing disabilities and mention "identify", "train", "support" and "integrate" as being important principles. Some strategies are suggested: (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).
Leprosy is diagnosed clinically by three principal signs (Lockwood 2002):
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 peripheral nerves that can easily be felt through the skin; and
a positive smear, i.e., evidence of the causative bacterium, M. leprae, using microscopic examination of a sample of tissue (skin smear).
There are two main forms of classification (Lockwood 2002a). They are the Ridley-Jopling scheme and the World Health Organization (WHO) paucibacillary/multi bacillary (PB/MB) classification.
This scheme classifies leprosy on a scale from 'tuberculoid' to 'lepromatous' based on the clinical appearance and bacterial index of lesions (Lockwood 2002a). '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 2002a).
This classification is based on the number of skin lesions (Britton 2004):
paucibacillary (PB) - up to five lesions
multibacillary (MB) - 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 classification system is the most widely used.
Nerve damage can happen before, during, and after chemotherapy treatment. It affects approximately 30% of people diagnosed with leprosy (2.6% with PB, 37% with MB, 2 years after diagnosis and MDT 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 2002b). These figures vary from country to country and between disease types.
Description of the intervention
As described above, leprosy is treated with multidrug chemotherapy. Other interventions, which we will not cover in this review, are aimed at treating immune reactions with corticosteroids, surgery, or both (Lockwood 2002).
The interventions of relevance to this review are those used in leprosy care which are aimed at the prevention and treatment of secondary damage to skin, nerves, and limbs. Such interventions include footwear, dressings (i.e., zinc tape, saline, iodine, gauze soaked in different ointments, dry dressings), self-care, and education (Lockwood 2002).
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 interventions may help in healing such ulcers (Srinivasan 1989).
Self-care includes daily management to reduce the effects of nerve function impairment (Lockwood 2002). Education, information, and empowerment of those affected by leprosy (and their carers) is part of some leprosy programmes (McDougall 2002).
As for dressings: ketanserin is an antihypertensive drug that is thought to decrease peripheral vascular resistance; this vasodilation might have beneficial effects on capillary haemodynamics, cause increased blood flow and enhance the healing of ulcers (Salazar 2001). Phenytoin is another topical dressing thought to enhance healing; the rationale behind this is that it "accelerates the formation and maturation of collagen fibres, stimulates fibroblast proliferation, and inhibits collagenase activity" (Bansal 1993). Zinc tape is also thought to enhance healing, as zinc might play a part in the healing of wounds; it remains intact when worn for a long period and tolerates moisture (Söderberg 1982).
Why it is important to do this review
An editorial note in WHO's Weekly Epidemiological Record says: "Leprosy control has benefited greatly from the implementation of MDT, which has enabled the disease to be cured and reduced the number of new G2D cases (with visible deformity or grade 2 disabilities); consequently stigma associated with leprosy and resultant discrimination against those affected has been reduced. There have also been economic benefits, with reduction of health system costs incurred for disability care, reconstructive surgery and rehabilitation. Nevertheless, surveillance of drug resistance, and research to develop shorter regimens and preventive agents, need to be continued or initiated in order to sustain the gains achieved and further reduce the disease burden due to leprosy" (WHO 2013).
"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 2002; Lockwood 2002a). Successful treatment of the nerve damage itself can be effective for preventing ulcer development. Corticosteroids have been used for this purpose (Lockwood 2002). However, a systematic review of three randomised controlled trials comparing prednisolone with placebo or comparing different doses of corticosteroids did not show a significant long-term effect (Van Veen 2007). Also, corticosteroids are not well tolerated by everyone and may cause harmful effects (Lockwood 2002). 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 in recent years to the management of leprosy programmes worldwide moving away from clinics dedicated to the treatment of leprosy, to primary healthcare services in general (Lockwood 2002; WHO 2010). However, despite the opportunity to lead 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 2002). People with leprosy must be and are involved in all stages of the leprosy programme, which involves "detecting cases early...reducing stigma, and promotion of social integration" (WHO 2011).
Why we present a new protocol
We have made the decision to update our review which was published in 2008 (Reinar 2008), by way of a new protocol because we wanted to reduce the numbers of pre-specified outcomes to those that are most clinically relevant, and include both randomised controlled trials and quasi-randomised trials.
We will include randomised controlled trials and quasi-randomised controlled trials where the method of allocation is such as alternation, date of birth, or case record number (Higgins 2011 ). This deviates from the previous protocol (Reinar 2003) in which we stated that we would only include randomised controlled trials, but it is consistent with the designs we actually included in our review. In our published review (Reinar 2008) we identified and included three studies with an alternating allocation procedure, four randomised controlled trials 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, and still is, that the risk of bias did not seem to be 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 somewhat elaborated by Chalmers (Chalmers 1999). As for randomised controlled trials, the results from a study by Pildal (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 equally 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 affirm in this protocol.