Leprosy

Synonym: Hansen's disease.

This disease is notifiable in the UK under the Public Health (Infectious Diseases) Regulations 1988.

Although rarely seen in the UK, leprosy is one of the most common causes of peripheral neuropathy worldwide. The first descriptions of leprosy are from India around 600 BC. In the fourth century, the disease was imported into Europe, where its incidence peaked in the 13th century.
Armauer Hansen discovered Mycobacterium leprae in Norway in 1873. It was the first bacillus to be associated with human disease.

It is an infectious disease caused by an obligate intracellular bacillus Mycobacterium leprae.

• The intracellular Mycobacterium act on the Schwann cells producing a chronic granulomatous reaction resulting in the destruction of both myelin and the underlying nerve cells.The damage to nerves and their protective outer layers leads to permanent neurological damage.
• It is only in the last decade that progress has been made in culturing the organism, defining its genomic sequence, and understanding the important differences in the host's reaction to the organism.
• The mode of transmission of the disease is uncertain, although it is thought that droplet transmission, contact with infected soil and contact with infected blood all occur.
• The severity of disease which develops in any individual is now known to due to the immune response of that individual to the organism. Genetic susceptibility to leprosy has been observed in some races and is thought to reflect a difference in immunological response to the mycobacterium.

The reported prevalence of leprosy has declined over the past decade in part due to a World Health Assembly initiative aimed at the elimination of leprosy as a public health problem. In 2002 WHO reported a prevalence of 1 per 10,000 as opposed to 12 per 10,000 15 years earlier.¹ Although it is probable that this reported prevalence probably underestimates the true incidence of the disease, the incidence has certainly fallen. The majority of cases are now centred in only 6 countries, with 64% of all cases occuring in India.

The symptoms of leprosy may develop in a very insidious fashion due to an average incubation period of approximately 7 years.Three features are required in order to make a diagnosis of leprosy:

• Reddish patches or hypopigmented areas of skin with reduced sensation.
• Thickened peripheral nerves.
• The presence of acid-fast bacilli in skin smears or biopsies.

The initial skin lesion, often referred to as indeterminate leprosy, may resolve spontaneously. If this fails to happen, the subsequent progression of the disease will depend on the patient's immune response to the organism. A spectrum of disease activity is described from tuberculoid leprosy, in which there is a low bacterial load and few skin lesions, to lepromatous leprosy, in which there is a high bacterial load and diffuse infiltration. This can affect not only the skin, but also areas such as the respiratory tract, the eye and lymph glands.² The mycobacterium has a preference for cooler temperatures and therefore it is the superficial structures rather than deep visceral organs which are usually involved.

Other neurological disorders that share similar features to leprosy will need to be considered in the differential diagnosis such as³:

• Mononeuritis muliplex
• Syringomyelia
• Other causes of neuropathy e.g. diabetes mellitus.

• The gold standard for establishing the diagnosis of leprosy, is the finding of M. leprae in biopsies of the skin lesions or slit skin smears. The smears are made by nicking the skin with a sharp scalpel and scraping it. Obtained fluid and tissue are thickly spread on a slide, stained by using the Ziehl-Neelsen method, and partially decolourised with 1% acid alcohol.
• Important serological tests for the detection of M. leprae antibodies or antigens are fluorescent antibody absorption test (FLA-ABS) test and phenolic glycolipid-1 (PGL-1) ELISA, which have been further simplified as dot ELISA and dipstick ELISA.
• In patients with pure neural leprosy, serum levels of PGL-1 may be helpful although only 50% will be seropositive.
• Patients seropositive for PGL-1 have an increased risk of relapse, and the level of PGL-1 may be used as an indicator of bacterial load in these patients.
• Nerve conduction studies may be useful in both establishing the diagnosis, and in monitoring the disease progress or response to treatment.

There are two different classification systems for leprosy:

Multibacillary (MB) or paucibacillary (PB) leprosy⁴

• Paucibacillary (PB) leprosy, negative smears at all sites, single or only a few hypopigmented and hypoaesthetic skin lesions.
• Multibacillary (MB) leprosy - either positive smears at any site, or multiple (>5) hypopigmented, hypoanaesthetic or erythematous skin lesions (sometimes poorly defined). Lesions may also be macules, papules or nodules.

Tuberculous or lepromatous leprosy

After exposure to leprosy and the incubation period, leprosy may fluctuate between various stages depending on the individual's cell mediated immune response or in response to therapy.

Transition toward the TT end of the spectrum is referred to as upgrading (and may lead to a reversal or type I reaction) and transition toward the LL pole as downgrading

1. Indeterminate stage - single skin lesion, frequently heals spontaneously
2. Tuberculoid leprosy (TT) - few skin lesions
3. Borderline tuberculoid leprosy (BT)
4. Borderline leprosy (BB)
5. Borderline lepromatous leprosy (BL)
6. Lepromatous leprosy(LL) - most severe stage, diffuse skin lesions and high bacterial load.

• This involves the use of effective antimicrobial drugs but also includes treatment of immune reactions and nerve damage.⁵
• Reduction in social stigma associated with disease at global, national and local levels increases self-reporting and allows timely intervention.⁶
• Specialist advice is available in the UK from a member of the Panel of Leprosy Opinion at the Department of Health.

Notification

• In the UK, all cases of leprosy must be notified under the Public Health (Infectious Diseases) Regulations, 1988.⁷
• Case reports are maintained on a central confidential register at the Communicable Disease Surveillance Centre.⁸

Staff and services

• Leprosy diagnosis and treatment are currently highly centralised activities, often conducted only by specialised staff.⁹
• To achieve long-term success leprosy control must be incorporated into national public health services.⁹
  The geographical coverage of leprosy services must also be expanded to improve access to local health facilities.
• Community healthcare staff must be well trained to enable them to accurately diagnose and manage leprosy.⁹

Education

• Leprosy is feared because of the associated deformities and social stigma. Fear of contagion also contributes to the enforced isolation of leprotic patients.
• Mass campaigns are needed to stimulate public awareness of the disease and its cure.⁹ Remote communities in particular, need access to information to reduce prejudice and stigmatisation.⁹
• People must accept leprosy as a simple curable disease and be aware of the availability of free and effective treatment.
• Patient education can also prevent neuropathic sequelae and improve compliance with medication.¹⁰

Early detection

• Early detection and treatment is essential for prevention of nerve damage.⁵
• Many patients delay seeking treatment until they have infected many contacts and developed irreversible deformities and disability.¹¹
• Public health initiatives must change the negative perception of leprosy and encourage people to come forward for treatment as soon as possible.⁹

Rehabilitation

• Assessment and monitoring of peripheral nerve function should be an integral component of the routine assessment of every patient.⁵
• After drug treatment or surgery, physical rehabilitation and attention to the social and psychological wellbeing of patients with disabilities is essential to facilitate reintegration into society.¹¹

Drug treatment aims to reduce morbidity and prevent complications.¹⁰

Multidrug therapy

• The introduction of multi-drug therapy (MDT) by the World Health Organisation (WHO) has produced dramatic changes in public control programmes and the management of leprosy.¹²
• In 1981 the WHO recommended the universal adoption of combinations of dapsone, rifampicin and clofazimine. Clofazimine has been withdrawn for its other indications but still available from Novartis via the WHO for treatment of the disease as part of MDT.
• MDT is now available free to all leprosy patients throughout the world.⁶

Schedule for treatment of multibacillary leprosy

• In the UK the WHO 3-drug regimen is recommended for a 2-year period.
• The schedule involves monthly, supervised treatment with rifampicin and clofazimine combined with daily self-administration of dapsone.¹³
• The WHO has suggested that MDT may be shortened to 12 months without compromising the efficacy of therapy. However limited data is available to assess long-term outcomes and relapse rates of such regimens. Many healthcare organisations have therefore opted to continue to promote a minimum of 24 months of treatment.¹²

Schedule for treatment of paucibacillary leprosy

• The WHO 2-drug regimen is followed for 6 months.
• Monthly, supervised rifampicin therapy and daily self-administered dapsone is recommended.

Efficacy of multidrug therapy

• Patients are non-infectious soon after the first dose of MDT and so further transmission of disease is prevented.⁶
• MDT regimens produce good clinical responses and relapse rates following completion of scheduled courses of therapy are very low.⁵
• Relapse rates are approximately 0.06% per year for multibacillary leprosy and 0.1% per year for paucibacillary leprosy.¹⁴
• The WHO estimates that early detection of disease and effective treatment has prevented disabilities in 4 million people, thus preventing significant social and economic losses.
• The MDT is established as a highly cost-effective health intervention.⁶

Antileprotic drugs

• Rifampicin
  • Is a mycobacterial RNA polymerase inhibitor.¹⁵ It has potent bactericidal activity and is the most effective antilepromatous agent available.¹⁴ It has good tissue penetration and gives an orange discoloration to body fluids.
  • Rifampicin can cause shock, acute renal failure and thrombocytopaenic purpura. If these occur, rifampicin must be immediately withdrawn and not reintroduced.
  • Rifampicin is a cytochrome P450 enzyme inducer and therefore interacts with the effects of many other drugs.¹⁵ It accelerates the metabolism of corticosteroids, sulphonylureas, anticoagulants, hormonal contraceptives and other medications.¹⁶
• Dapsone
  • Is structurally similar to the sulphonamides and exerts its bactericidal effects by inhibiting the dihydropteroate synthetase and therefore blocking microbial folate synthesis.
  • Dapsone is well absorbed from the gastrointestinal tract and widely distributed throughout the body.¹⁷
  • Side-effects are common and may include haemolysis, agranulocytosis and hepatic dysfunction (see drug monograph).
  • Dapsone should be avoided in patients with previous allergic reaction to sulpha-containing medications.¹⁰
• Clofazimine
  • Is a substituted iminophenazine bright-red dye.
  • It is given orally and accumulates in the mononuclear phagocyte system.
  • Clofazimine binds to mycobacterial DNA and inhibits microbial growth.¹⁸
  • The bacteriostatic effect is delayed and the exact mechanism of action is unknown. Clofazimine also has anti-inflammatory properties.¹⁵
  • It is generally well tolerated in doses used to treat leprosy. Adverse effects are usually dose related and reversible when the drug is discontinued. Common side-effects include gastrointestinal upset, dark discoloration of skin, cornea and body fluids, pruritus, rash and skin dryness.¹⁹
• Other drugs
  • Second-line antileprotic drugs can be used for patients intolerant of first-line therapy. Treatment should be under direct supervision at a specialist centre.²⁰
  • A monthly combination of rifampicin, ofloxacin and minocycline has been used for multibacillary and paucibacillary disease with good clinical outcomes. However the long-term relapse rates are unknown and so close follow-up is essential.⁵
  • Single dose therapy using rifampicin, ofloxacin and minocycline is in use worldwide as alternative treatment of single-lesion paucibacillary leprosy.¹²
  • Both multiple-dose MDT and single dose treatment achieves high cure rates but multiple-dose therapy achieves higher long-term cure rates and is therefore still the treatment of choice in the UK.

• For many years dapsone was the only effective antileprotic drug available. Its long-term use as monotherapy led to selection of dapsone-resistant M. leprae.⁹
• MDT was introduced specifically to prevent the emergence of further drug resistance, particularly against rifampicin.¹⁴ No resistance to the recommended MDT regimen has yet been documented.
• However resistance to multiple antileprotic drugs has been detected among patients receiving non-standardised treatment. Drug susceptibility testing is thus recommended in cases of relapse, where inadequate initial treatment is suspected.²¹

Management of reactions

• Immune-mediated reactions occur secondary to changes in the host's immune status¹² and may occur before diagnosis, during treatment or after cure.⁵
• Full dose MDT should be continued throughout all reversal reactions with the addition of anti-inflammatory therapy, analgesia and physical support as necessary.¹²
• Type I or reversal reactions are associated with an increase in cell-mediated immunity. Early detection is essential to avoid irreversible peripheral nerve damage.¹² The frequency of such reactions is increased during the early stages of treatment of multibacillary leprosy.²⁰
• Type I reactions should be treated immediately with high-dose prednisolone. Rest and the timely use of splints and physiotherapy are also recommended.¹⁰
• Erythema nodosum leprosum
  • Type II or erythema nodosum leprosum (ENL) reactions are systemic inflammatory responses to the deposition of extravascular immune complexes.¹²
  • The frequency and severity of ENL reactions is significantly reduced in patients on MDT but may still occur during or after treatment.²⁰
  • Severe ENL reactions also require corticosteroids but mild reactions may respond to aspirin or chloroquine.
  • Thalidomide has been used successfully in the management of ENL reactions, for men and post-menopausal women. Its role is limited by teratogenicity and must only be used under specialist supervision.²²

Pregnancy

• Hormonal and immunological changes during pregnancy cause suppression of cell-mediated immunity and worsening of symptoms. Infants born to mothers with leprosy have low birth-weights and an increased risk of developing the disease.
• The WHO therefore recommends that MDT be continued during pregnancy.¹⁰ However the drugs used in the treatment of leprosy are not without risk and treatment should be under specialist supervision.
• Rifampicin reduces the efficacy of hormonal contraceptives so alternative contraceptive advice should be offered.¹⁶
• High doses of rifampicin may be teratogenic and it is not recommended for use during the first trimester.
• Dapsone may cause neonatal haemolysis and methaemoglobinaemia. If necessary it should be prescribed to pregnant women in combination with folic acid.
• Clofazimine may cause discoloration of the skin of breast-fed infants.
• The use of thalidomide remains strictly contra-indicated in women of childbearing potential.¹⁰

Chemoprophylaxis

• A recent study has shown that close leprosy contacts that are treated with rifampicin have lower rates of subsequent disease.²³
• Other studies of leprosy chemoprophylaxis for contacts of index cases have failed to show any significant protection.
• The WHO does not currently recommend the routine use of chemoprophylaxis but suggests that contacts are simply monitored for signs or symptoms suggestive of disease.¹⁰

Surgery

• Nerve decompression is indicated when signs of peripheral nerve entrapment have not resolved after 3-4 weeks of steroid therapy and if there are signs of nerve abscess or chronic entrapment. Peripheral nerve reconstruction may help restore sensation to the hands and feet and nerve grafts may be helpful for patients with localised nerve lesions.
• Arthrodesis or tenodesis may be necessary to correct clawing or stabilise joints and chronically diseased limbs may even require amputation.
• Cosmetic surgery may be effective for nasal reconstruction, replacement of eyebrows or excision of redundant ear lobe or eyelid skin.¹⁰

• Pentoxifylline and clofazimine have shown encouraging results for the treatment of severe type II immune reactions and are currently undergoing large clinical trials.¹²
• Mycobacterium w (Mw) vaccine has shown reasonable efficacy in eliciting immunoprophylactic responses in household contacts of leprosy patients, particularly in children.²⁴
• Therapeutic roles for leprosy vaccines and other immunomodulatory agents are also under investigation. It is believed that enhancement of defective host cell-mediated immunity improves clearance of mycobacteria.¹⁰
• However the use of immunotherapy in the treatment of established leprosy is currently hampered by an increased frequency of type I reactions.¹²

• If left untreated, leprosy may result in blindness and physical deformity.
• Despite treatment with MDT, reactive states may still lead to neurological damage producing Charcot's joints and other deformities.
• Secondary amyloidosis is now rare in patients treated with MDT.

• The prognosis for patients adequately treated with MDT is very good.
• Relapse with MDT is 0.1% per year for PB and 0.06% per year for MB on average, with a low frequency of adverse effects.¹⁰
• Relapse may occur as late as thirteen years after treatment, however a second course of MDT is likely to produce a good response.
• Nerve damage may still occur in a few despite appropriate treatment due to a reactive state.

• Prevention of leprosy by vaccination would provide a valuable public health tool. However there is currently no specific vaccine effective against leprosy.⁹
• The Bacillus Calmette-Guerin (BCG) vaccine was originally aimed at prevention of tuberculosis but is actually more effective against leprosy.⁹ The efficacy of the BCG vaccination against both tuberculosis and leprosy is hugely variable, depending on the study population.²⁵
• The BCG generally offers 40-50% protection against leprosy.⁹ The addition of killed M. leprae to the BCG vaccine is believed to increase its efficacy.
• The International Committee of the Red Cross (ICRC) bacillus vaccine provided 65-70% protection in efficacy trials in India.¹⁰ It is considered to be the most effective vaccine against leprosy and is associated with few adverse effects.
• None of these vaccines have provided a reproducible level of efficacy that could be considered for a cost-effective worldwide public health strategy and are not recommended by the WHO.⁹