Abstract

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Leprosy is a chronic infectious disease caused by a rod-shaped bacillus, Mycobacterium Leprae. This disease was used to be considered incurable. This disease will cause patients suffering from it to have skin lesions at the extremities, having physical deformities of the fingers, toes and also face. Diagnosis of this disease is hard because the bacillus have a long incubation period. The signs and symptoms will only show a few months or maybe years after infection. However, once the disease is diagnosed, chemotherapy by multidrug therapy of dapsone, rifampicin, clofazimine and other chemotherapy drugs will be given to treat the disease. The treatment will be long term ranging from six months to two years, depending on the seriousness of disease. Single dose of chemotherapy drug or Bacillus Calmette-Guerin (BCG) vaccination can be used as prophylaxis against leprosy.

Introduction

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Leprosy, which is also known as Hansen’s disease, is a chronic infectious disease caused by Mycobacterium Leprae (M. Leprae).[1] Analysis of the DNA of M. Leprae strains suggests that this bacterium originated in Africa and has spread to Asia and South America.[3]
Before 300 B.C., leprosy was still unknown in Greece and the Western. Andersen wrote in his thesis that the disease was brought to the Mediterranean littoral by the soldiers of Alexander the Great returning from the Indian campaign in 327-326 B.C.[2] J. G. Andersen published a doctoral thesis on the history of leprosy based on the results of his own linguistic, osteo-archaeological, and clinical researches. He concluded that the swellings referred to in the Eberspapyrus (c. 1552-1350 B.C.) were actually signs of leprosy.[2]
The complexity of the Leprosy disease has brought a Danish general practitioner, V. Moller-Christensen, to a cemetery attached to a medieval monastery near Nestvedin Denmark (cemetery from about A.D. 1175 to 1544). Some hundreds of people buried there showed bony extremities representing the changes in patients with leprosy. The two prominent characteristics were the advanced destruction of the phalanges which involves the erosion of the anterior nasal spine and also the alveolar process of the maxilla. This condition was named as faciesleprosa, or the Bergensyndrome.[2]
The way M. leprae is transmitted up till now is still unknown. There are still no effective vaccine used to prevent this disease from spreading and practical tools used for early diagnosis of clinically unapparent disease has yet to be produced.[5] Leprosy can affect individuals at any age but most common in individuals between the ages of 10 to 20.[19]
Leprosy can be classified by using two schemas that is the 5-category Ridley-Jopling system and a simpler more commonly used the World Health Organization (WHO) standard.
The Ridley-Jopling system is used worldwide and is also commonly used in clinical studies of leprosy. It is also more useful in choosing the proper treatment regimens and also in the assessing of the risk of acute complications.[6] Illustration 1 shows the classification by Ridley-Jopling System.
WHO on the other hand recommends classifying leprosy based on the number of lesions and the presence of bacilli on a skin smear. It is useful when biopsy is unavailable. Paucibacillary leprosy is represented by 5 or fewer lesions with absence of the organism on smear. Paucibacillary leprosy includes the tuberculoid (TT) and borderline tuberculoid (BT) categories derived from the Ridley-Jopling system.[6]
In contrast, the Multibacillary leprosy is represented by 6 or more lesions and bacilli visualisation on smear done. Lepromatous leprosy (LL), borderline lepromatous leprosy (BL), and midborderline leprosy (BB) on the Ridley-Jopling scale are included in this category.[6]
Leprosy is also understood as being a two conjoined diseases. The first one is a chronic mycobacterial infection that will result in an astonishing range of cellular immune responses in humans. The second one is a peripheral neuropathy that is caused by the infection and the immunologic events followed by it, but it’s cycle often extend many years beyond the cure of the infection and may be followed by severely devastating physical, social, and psychological consequences. People who deals with this disease (clinicians, researchers and etc.) should always be aware of this concept regarding leprosy.[5]
During the first Leprosy Congress held in Berlin in 1897, it was agreed that Leprosy is incurable. Later on, this perception towards Leprosy was eliminated after scientists realized sulphones is effective against the Leprosy disease. Dapsone, sulphormethoxine, clofazimine, rifampicin seems to have bacteriostatic effect when tested with M Leprae in the mouse foot-pad.[2]
In 1981, WHO suggested that all patients should receive multidrug therapy. Dapsone monotherapy was effective in the earlier times and was started in the 1940s. This treatment required lifelong administration. Unfortunately, in 1960s widespread resistance was observed and reported.[3]
A delay in diagnosis can have crucial negative consequences, such as increased risk of nerve damage. Unfortunately, there is no predictive test for the level of nerve damage and also no firm proof for the best treatment of this disease. WHO has set an aim or better yet a target in order to decrease the number of cases of leprosy with grade 2 disability at diagnosis, but the possibility of reporting disability needs to be assessed accurately.[3]

Epidemiology

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Leprosy is a disease that is rarely fatal and the most commonly consequences due to this infection is the nerve impairment. 33-56 percent (%) of patients that were detected with leprosy has nerve impairment as the sign of the disease. In United States (US), an average of 150 cases has been diagnosed each year. Most of this infection was found in immigrants from Florida, Texas, Mexico, and New York City. Around 85% of this disease detected involved patients who have lived in the foreign countries, mostly in Asia, Africa and Latin America.[6]
In 1991 WHO's governing body, the World Health Assembly (WHA) approved a resolution to eliminate leprosy as a public health problem by 2000. Elimination of leprosy as a public health problem is defined as the disease occurring in one individual per 10 000 persons.[7]
Data from the WHO stated that, 286,063 cases been registered due to the leprosy infection starting from 2005 until present. Eventhough the number of cases is high, but from 2001 to 2004, it has been detected that the number of case decline gradually. Leprosy was once known as an endemic worldwide and a no racial preference disease. But, in a meantime, the incidence of leprosy in northern Europe and North America dropped dramatically in late 1800s and the disease now have been reported mostly in tropical areas.[6]
Leprosy is a disease of poverty so access to diagnostic and rehabilitation facilities, treatment as well as early prevention of disability, must be ensured. Approximately, 250 000 new cases are being registered each year and about 15 million people have been subjected to multidrug therapy, and an estimated 2 million people have been prevented from developing disabilities and this is could be partly due to the prevalence values being halved because of the period of the treatment being reduced from 24 months to 12 months.[3
Malaysia is not an endemic country in general. In 1950, a unit was started at the Sungai Buloh Leprosy Settlement that is focused on the research of Leprosy disease. In 2005, the prevalence rate for leprosy according to WHO in Malaysia was 0.32 per 10,000 people, and it was in the same year that 263 new cases were reported in the country, resulting in a new case discovery rate of 1.1 per 100,000 people.[8]

Causes

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Leprosy is caused by the rod-shaped bacillus, M.leprae, which is an obligate intracellular organism.[4][9] Most of the people infected with leprosy are not-infectious since these mycobacteria stay inside human or animal cells. However, leprosy can be infectious when these mycobacteria are excreted out from nasal mucosa of the host, provided treatment with multidrug therapy is not given yet. These bacteria are spread from infected person to susceptible person in the form of nasal secretions or droplets.[3]
Droplets which are contaminated with these bacteria are ejected out of nasal passage and reach the nasal passage of the other people to start the infection. Also, M. leprae can enter the host body through wounds or broken skins, from which infection by mycobacteria begins and leprosy develops.[4] Nevertheless, this disease is difficult to be identified form the aspects where and when the patient is infected because it has a long incubation period.[9]
Some studies had been done show that leprosy in patients is probably not only caused by transmission itself but by subclinically infected patients and by contacts of patients with leprosy. Out of these three factors, contacts of patients with leprosy have been the main determinant in leprosy incident. Contacts in this case can be comprised to household and neighbor contacts. Household contacts are people who lived with a patient in the same household (house). Neighbour contacts are people who live either in a house adjacent to the patient’s house (neighbour 1) or in a house adjacent to neighbor 1 house, in both cases with a distance of less than 50 meters between the houses.[25]
People who are in close proximity or contact with the infected patients are rendered higher risk of developing leprosy. The probability of being infected by the mycobacteria is dependent on the closeness of contact, with the close household contacts being at the highest risk.[3]
Eventhough, human-to-human transmission is the main source of infection, there are three other species that can carry and transfer M. leprae to humans but this is a rare occurrence. They are chimpanzees, mangabey monkeys, and nine-banded armadillos. This type of the disease is known as chronic granulomatous disease and is very much similar to tuberculosis, because it will result in inflammatory nodules (granulomas) in the skin and nerves as the disease progresses.[4]
Besides, increased susceptibility to leprosy is related to genetic factor. A locus within gene PARK2/PACRG is said to be able to cause human population susceptible to M. Leprae. This has been proven by the analysis of Vietnamese patient population and also analysis on Brazilian families with one or more family members having leprosy.[5]
Another gene which is said to cause susceptibility to leprosy is NRAMP1. NRAMP1 is a gene for macrophage protein 1. This protein is said to influence the viability and/or replication of pathogens in macrophages which will lead to leprosy. This is reported after a study was done on families with multiple leprosy cases.[5]

Sign and Symptoms

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Generally, signs and symptoms are two different components that should be identified in a disease. In medicine, basically, a sign is classified as an objective, while a symptom is subjective.[11] A sign is a measureable component or can be counted while symptoms are non-measurable or uncountable.[11] Unfortunately, the early signs and symptoms of patients having leprosy is very small and occurs very slowly, usually it will take over years to develop the sign and symptoms.[4] But, the signs and symptoms may vary with different classification of leprosy.[12]
The signs and symptoms of leprosy will develop slowly and subtle, and will be fully develop within six months to 40 years. Leprosy may lead to skin damage and also the peripheral system.[4] The skin will thicken and also the peripheral nerves.[12] The involvement of peripheral nerves will lead to muscle weakness, and the patient will experience clawed deformities, contractures and foot drop.[9][12][13
Leprosy affects the skin and this is known as the indeterminate type of leprosy. This condition is represented by swollen reddish patches on the body surface. At this point the body’s immune system will try and get rid of the bacteria from the body and it may or may not succeed. If it succeeds then the red patches will be gone. If it does not then the bacteria will multiply and their number will increase significantly. The indeterminate type will then become either the lepromatous (LL), tuberculoid (TT) or borderline type (BB).[4]
The tuberculoid (TT) type of the disease on the other hand will affect the nerves at the extremities of the bodies[4] or also known as paucibacillary leprosy because of the small number of bacteria in the skin.[6] Leprosy affects nerves that will alter the function of sweat glands and sebaceous glands that basically keep the skin moist.[4] Individuals with vigorous cellular immune response to M leprae will tend to develop the tuberculoid (TT) form of the disease that is characterized by the signs and symptoms that were mentioned. The number of skin lesions is limited and can be dry and hypoesthetic. Nerve involvement is usually asymmetric.[6]
The lepromatous (LL) type will be represented by patients that seem to have a very swollen face which is due to the thickening of the skin around the nose and the face. If it is not treated then the cartilage will become destroyed.[4] Individuals with minimal cellular immune response will develop the lepromatous (LL) form of the disease, which is characterized by extensive skin involvement. Skin lesions are often described as permeated nodules and plaques, and nerve involvement tends to be symmetrically distributed. The skin lesions tend to develop in the cooler areas of the body such as the groin, axilla, and scalp. This is because the organism is has optimal activity in an environment with a temperature range of 27-30 0C. This form of the disease is also known as multibacillary leprosy due to the large number of bacteria found in the lesions and the results of skin tests with antigen from killed organisms will be nonreactive. Patients may also present show signs and symptoms from both categories but later on they will usually evolve to one of the types.[6]
Furthermore, patients will loss sensation, like heat (the patient will not be able to distinguish whether it is hot or cold), touch, pain or even pressure.[4][12] Ulceration and lesions of the skin indicates that the person showed some signs of the leprosy. Even though the patient suffer from the ulceration of the skin, but the ulcer is painless and the patient will not experience the pain.[4]
The eyes also will also be affected by leprosy. Eyes will be damaged and this will lead to pain and eyes will turns red. Moreover, there will be difficulties in closing the eyelids and corneal ulcers will also present, but the most critical sign is blindness.[4][12] However, a study done in 1995 shows that eye involvement in leprosy is low compared to many other surveys and visual loss is more likely due to other disease or advancing age.[14] Patient also will also experience the loss of eyebrows and eyelashes. The nose also will be affected by having destruction of the nasal cartilage. Testicular involvement with the disease will lead to sexual dysfunction or sterility.[12]

Diagnosis

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Leprosy is a infectious disease caused by a bacillus, M. leprae[7] which has a long incubation period. Diagnosis of leprosy is most commonly based on the clinical signs and symptoms. In an endemic country or area, an individual should be regarded as having leprosy if he or she shows one of the following cardinal signs; skin lesion consistent with leprosy and with definite sensory loss, with or without thickened nerves and positive skin smears.[15]The clinical spectrum of leprosy is determined by the underlying immunological response of the host against M.leprae. The dynamic nature of the disease may lead to spontaneous fluctuations in clinical states that are known as leprosy reactions.[16]
The majority of cases of leprosy are diagnosed by clinical findings, especially since most current cases are diagnosed in areas that have limited or no laboratory equipment available. Hypopigmented patches of skin or reddish skin patches with loss of sensation, thickened peripheral nerves, or both clinical findings together often comprise the clinical diagnosis.[4] Microscopical examination of the skin or nerve lesion plays a major role in the diagnosis of leprosy. A typical clinical lesion should be biopsied (skin smears). The primary characteristics to be recognized are histological patterns of the host response in hematoxylin- and eosin-stained sections, the involvement of cutaneous nerves, and the identification of acid-fast bacilli (AFB) within nerves using the Fite-Faraco modification of the carbol fuchsin stain.[5
According to the Ridley-Jopling classification's, the histological spectrum of classification consists of full tuberculoid (TT), borderline-tuberculoid (BT), mid-borderline (BB), borderlinelepromatous (BL) and lepromatous (LL). The microscopical diagnosis of multibacillary leprosy such as BL or LL type is easy due to the presence of numerous AFB.[1]
However, the diagnosis of early leprosy such as indeterminate and tuberculoid leprosy is often difficult clinically as well as histologically. Serial sections of the biopsied tissue may be necessary to detect granulomas, around nerve bundles. Immunocytochemical staining using S- 100 protein as a nerve marker has been attempted in leprosy. It is a valuable marker to detect the nerve fibres. Fragmented and dissociated nerve fibres in the granuloma of tuberculoid leprosy may not be easily seen in routine H&E sections. S-100 staining is useful to pathologists who only occasionally get biopsies from leprosy patients.[1]
Other than that, there are also use of bioinformatics and comparative genomics to identify potentially antigenic proteins for diagnostic purposes. This approach defined three classes of proteins: those restricted to M. leprae (class I), those present in M. leprae with orthologues in other organisms besides mycobacteria (class II), and exported or surface-exposed proteins (class III).[17]
Serological tests for detection of infection and to monitor progress under treatment have been of interest for some time. Such tests might also be useful to identify contacts, to monitor transmission in the community, and to guide treatment.[3]
However, there is a test named the lepromin test which is often the cause of confusion and misplaced diagnostic expectations. The lepromin skin test is not diagnostic of leprosy or exposure to M. leprae. The test response is measured as in duration (in mm) 4 weeks after injection and is ideally also evaluated by biopsy and histopathological examination of the test site. This test provides a measure of the individual’s ability to mount a granulomatous response against the mixture of antigens present. Responses to lepromin are not leprosy specific; many individuals who have never been exposed to M. leprae will also develop a positive lepromin reaction.[
Today, most endemic countries are striving to fully integrate leprosy services into existing general health services. This is especially important for those under-served and marginalised communities most at risk from leprosy, often the poorest of the poor.[18]
An early diagnosing is very important because it can limits damage, prevents a person from spreading the disease and also allows the person to have a normal lifestyle.[9] Late diagnosis leads to continued transmission and to increased risk of disability.
Factors associated with late diagnosis include delay by patients in presenting and delay by health services in making a diagnosis. Reasons behind patients delaying presentation vary from setting to setting, but stigma is likely to play a part in many cases. In some countries, stigma is promoted by legislation against leprosy patients. Other inequalities also affect people with this disease. Reports from Ethiopia and Bangladesh have shown that women experience longer delays than men in diagnosis and, therefore, frequently have a higher degree of nerve damage and disability at diagnosis.[3]

Treatment

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Most of cases of Leprosy mainly clinically diagnosed are commonly treated with antibiotics. However, recommended antibiotics, dosages, and length of time of administration are still based on the classification of the disease and whether patient is under supervision of a healthcare professional.[4]
Leprosy is said could be treated by thalidomide, steroid and also clofazimine. Thalidomide is chosen as a treatment for the management of leprosy for relapsing or steroid-depending course. Its efficiency is due to its anti- tumour necrosis factor (TNF)-? which cause pathogenesis in leprosy. However, precaution is needed towards women in child-bearing age. Short courses of steroids can also be used for management of leprosy and is required if neuritis is present. Clofazimine can also be used as a treatment. However, it has limitations of being slow to act and not complete treatment of leprosy.[16]
Since 1950s, dapsone or diaminodimethyl sulfone was introduced as standard antimicrobial chemotherapy for leprosy. Dapsone is now still being used widely for treatment of multibacillary and paucibacillary forms of leprosy. However, the long-term monotherapy of dapsone had result in poor compliance, subsequently leading to the emergence of dapsone-resistant leprosy.[5] Consequently, this result in treatment failures and resistance levels reported to be as high as 40%. Dapsone was used as a standard drug in the Multi Drug Therapy (MDT) regimen later.[20] Treatment of leprosy with only one antileprosy drug resulted in the development of drug resistance to that particular drug. Treatment with dapsone or any other antileprosy drug used as monotherapy should be considered as unethical practice.[21] However, recently, WHO suggested that single-dose treatment of patients with only one skin lesion with rifampicin, minocycline (Minocin), or ofloxacin (Floxin) is effective.[19]
Since the year of 1982, as a treatment of leprosy, WHO had recommended multidrug regimen, Multi Drug Therapy (MDT). For MDT, usually more than one antibiotic is given together for a more effective treatment.[9] In order to reach a prevalence of less than one leprosy case per 10,000 population, treatment with MDT still remain an important element in the strategy to treat and cure leprosy as a public health problem. It is said that MDT is highly effective, and more than 11.2 million patients have receiving it.[22]
The National Leprosy Control Centre has modified the regimen and this modified regimen is used in Malaysia.[1] A variety of different kinds of antibiotics such as rifampin, dapsone, clofazamine, fluoroquinolones, macrolides, and minocycline are often used to kill the bacteria that cause leprosy.[9]
The regimens recommended by the World Health Organization of six or 24 months’ multidrug treatment produce good clinical responses and low rates of relapse. Among the antibiotics, rifampicin, dapsone, and clofazimine are the most common three antibiotic drugs being used.[23]
Paucibacillary leprosy should be treated for 6-12 months with dapsone 100 mg/day unsupervised plus rifampin 600 mg/month supervised. This regimen should be followed by treatment with dapsone as monotherapy for 3 years in patients with tuberculoid leprosy or 5 years in patients with borderline lepromatous leprosy.[23]
Multibacillary leprosy should be treated for 24 months with dapsone 100 mg/day unsupervised, clofazimine 50 mg/day unsupervised, and rifampin 600 mg plus clofazimine 300 mg/month supervised.[23]
Corticosteroids have been used to treat nerve damage associated with leprosy, but a recent review of 3 randomized controlled trials (RCT) shows no significant long-term effect. Prednisolone is believed to minimize pain and acute inflammation. The recommended initial dose is prednisolone 40 mg daily.[23]
Illustration 2 shows the summary of dose needed to be taken daily monthly and also the duration of treatment based on different types of leprosy. Among these rifampicin acts as the most crucial antileprosy drug so far. Hence, it is included in the treatment of both types of leprosy.[22]
Monthly rifampicin, ofloxacin, and minocycline in combination has been used in both multibacillary and paucibacillary disease, with good clinical responses.[22]
MDT has been very practical and successful for treatment of both multibacillary and paucibacillary leprosy, and the overall number of registered cases worldwide has fallen dramatically.[5]

Prevention

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Since leprosy is a disease caused by M. leprae, one of the prevention taken is by vaccination which is by Bacillus Calmette-Guerin (BCG) vaccination. Vaccination with BCG protects people from developing leprosy plus neonatal BCG vaccination given to prevent tuberculosis has probably contributed substantially to the decrease in prevalence of leprosy. However, since BCG is a live vaccine and therefore, it should be avoided in people infected with HIV.[3]
Back in the year 1982, MDT was introduced by WHO. However even after 20 years of MDT, case detection rates do not show any decrease in value. Even though the number of registered cases have fallen from 5.4 million worldwide in 1985 to below 1 million in 1998, 600 000 new cases are still being discovered annually. Even though the prevalence of leprosy may have fallen dramatically, the case detection rate still remained almost constant. There is a fall in incidence of leprosy in some countries. However, it might be due to socio-economic improvements or the use of BCG vaccinations.[24]
Chemoprophylaxis which is the administration of chemical or medication to prevent disease or infection seems to be effective in lowering the incidence of leprosy in household contact. Back in 1960s and 1970s, the usage of dapsone and acedapsone as chemoprophylaxis was extensively investigated. Dapsone is effective against most strains of M. leprae but perceived problems of dapsone resistance limited the development of chemoprophylaxis regimens using dapsone alone.[25]
Rifampicin is then later investigated for chemoprophylaxis. Single-dose rifampicin can prevent progression of disease in people infected with leprosy but only in non-close contacts with low bacterial infection. However, based on the study of rifampicin prophylaxis against leprosy conducted at a 30-archipelago in the Flores Sea in Indonesia showed that prophylaxis given to the whole community was associated with a reduced incidence of leprosy. In contrast prophylaxis is given only to household and neighbor contacts do not have a detectable effect on leprosy incident.[25] This shows that chemoprophylaxis with rifampicin is highly effective and can be widely used in prevention of leprosy. However, it is more cost-effective when used in household contacts than in general endemic communities.[3]
Due to fears of resistance with use of monotherapy, this had led to a suggestion that one or two doses of 600mg rifampicin, 400mg ofloxacin and 100mg minocycline (ROM) should be used instead. However, the cost of study using a single dose ROM is far more expensive.[3]
With the development of a more potent prophylaxis, combined single dose chemotherapy and BCG to boost the immune response may give an added effect on reducing incidence rates, preventing leprosy infection.

Conclusion

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As a conclusion, leprosy is no longer a threat to human population for treatments are effective and very promising. However, due to the difficulties in diagnosing leprosy during its early stage because of its long incubation period, many patients do suffer from the effects of leprosy. To overcome this problem, diagnosis of leprosy should be improved in order to detect the disease at its early stage so that early treatment could prevent effects nerve involvement and also physical deformities. Other than that, leprosy vaccines are not effective enough to eliminate leprosy disease.

Acknowledgement

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We are able to complete our assignment for FAR241 Antimicrobial Therapy on Leprosy successfully. We would like to take this opportunity to express our appreciation to everyone who was involved directly and indirectly in assisting us to complete this assignment.
We would like to thank Dr. Amin Malik Shah bin Abdul Majid, the coordinator of the course FAR241 Antimicrobial Therapy for giving us a chance to have a go on this assignment. This assignment not only taught us more about leprosy but it also allow us to have a chance to work together as a group, strengthening bonds between course mates.
Furthermore, lots of thanks to Prof. Gam Lay Harn and Dr. Vikneswaran A/L Murugaiyah for spending their time to review our assignment. We hope that our work did meet your expectations.

References

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Source(s) of Funding

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Competing Interests

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