Uncommon Infections

Mycobacterium leprae

LEPROSY (Adapted from notes kindly supplied by Professor Diane Lockwood) 

Introduction

Leprosy is an infectious disease caused by Mycobacterium leprae which affects skin and peripheral nerves. It is readily treatable with combined antibiotic therapy but the immunological complications of leprosy frequently cause nerve damage even after effective antibiotic treatment. Leprosy occurs throughout the Tropics and sub Tropics. Despite effective antibiotics and elimination campaigns there are still about a million people globally with leprosy. New cases continue to present at a steady rate of 600,000 globally per year. The incubation period of leprosy may be up to 15 years so we can expect to see cases presenting for many years yet.
  

Classification

Leprosy is an unusual disease in that clinical manifestations are determined entirely by the host immune response. There is no evidence for different types of Mycobacterium leprae.

  

The clinical presentation of disease forms a spectrum - at one end of the spectrum is tuberculoid disease. These patients have a very good cell mediated immunity, eliminate mycobacteria with granulomatous damage to their skin and peripheral nerves. You can imagine these patients have very localised disease and have only one skin lesion or one peripheral nerve involved. At the other end of the spectrum are patients with lepromatous disease. These patients have no cell mediated immunity for Mycobacterium leprae and therefore the organism multiplies unchallenged. These patients have a very heavy load of bacteria in their skin, nerves and nasal mucosa and have diffuse and widespread disease. In between the tuberculoid and lepromatous poles one has borderline forms of the disease. Patients with borderline tuberculoid leprosy will have some cell mediated immunity which is not quite as good as that at tuberculoid end. There is therefore some bacterial multiplication and patients will have several skin lesions. At the borderline lepromatous point on the spectrum, patients have a combination of some cell mediated immunity and moderate bacterial multiplication. These patients have numerous diffuse lesions.

 

Understanding the spectrum of disease helps with the management of leprosy. Patients at the tuberculoid end of the spectrum will need shorter treatment with antibiotics whereas patients at the lepromatous end of the spectrum need longer treatment. Patients at the lepromatous end of the spectrum are also responsible for spreading infection in the environment. Patients at the extreme ends of the spectrum, tuberculoid and lepromatous, are stable and will stay in those clinical forms. The patients with borderline forms are immunologically unstable and may move up or down the spectrum.

    

Characteristics of Mycobacterium leprae

We remain unable to grow Mycobacterium leprae in the laboratory despite efforts to do so over more than 120 years. The only animal models that we have are the nine-banded armadillo in which extensive multiplication takes place with heavy bacterial loads in the liver and spleen. The footpads of nude mice can also be used to grow organisms for testing drug sensitivity but this is a very laborious process. This organism is very unusual in having a very slow doubling time about 14 days. It is also very hardy and has been known to survive for up to five months on a South Indian laboratory bench!

 

For tuberculoid leprosy the incubation time is two to five years, for lepromatous leprosy it is nine to fifteen years. Of patients seen here in London some had symptoms for up to fifteen years. The importance of the long incubation time is that patients may present with leprosy long after they have left a leprosy endemic area.

  

Diagnosis of leprosy
Leprosy is diagnosed when the following features are present:

1. Skin lesion typical for leprosy. This may or may not be anaesthetic.

2. Thickening of peripheral nerves.

3. Presence of acid fast bacilli in skin smears.

The features present in any one patient will depend on the type of leprosy that they have. A patient at the tuberculoid end of the spectrum will have a single anaesthetic lesion but negative skin smears. A patient with lepromatous leprosy will have nodules or infiltration that will not necessarily be anaesthetic but they will have positive skin smears. Histology is critical in the diagnosis of leprosy. At the tuberculoid end of the spectrum abundant granulomas will be seen together with destruction of dermal nerves and parasitic infiltration of nerves. At the lepromatous end there are abundant active macrophages with heavy mycobacterial load.

 

Antibody tests are not useful in the diagnosis of leprosy. Lepromatous patients will have antibodies to Mycobacterium leprae but only 50% of tuberculoid patients will have antibodies. Furthermore the current PCR primers which have been tried for leprosy do not have sufficient sensitivity or specificity for diagnosis. Remember also that M. leprae cannot be cultured from skin biopsies.   

 

Clinical forms and presentation of leprosy
Cutaneous signs. The commonest skin lesions in leprosy are macules and plaques which may occur anywhere. In tuberculoid leprosy the lesions are usually well defined with elevated borders and central clearing. In lepromatous leprosy a diffuse infiltration of the skin occurs, which eventually results in the classical 'leonine facies'. The skin thickens over forehead, eyebrows and eyelashes are lost, the nose becomes misshapen or collapses, ear lobes thicken and the upper incisor teeth fall out.  Erythematous infiltrated plaque of tuberculoid leprosy
   

Infiltrated plaques of lepromatous leprosy resulting in leonine appearance

  
Nerve damage Nerve damage in leprosy occurs in two settings. It occurs in the skin where dermal nerves supplying sensation and temperature are lost. Small autonomic fibres are also destroyed so sweating is lost in these lesions as well. The peripheral nerve trunks are also affected in leprosy. Thus, one will see patients with muscle weakness and anaesthesia that is typical for peripheral nerve injuries such as ulnar or common peroneal nerve lesion.

 

The nerves that are particularly affected are the ulnar at the elbow, the median at the wrist, the common peroneal at the knee and the posterior tibial and sural nerves at the ankle. The older text books all cite the ulnar nerve as being the most commonly involved nerve in leprosy. It is only recent detailed cohort studies that have shown that in fact the posterior tibial nerve is the most commonly involved nerve. This would fit with the experience with anybody who has visited a leprosy hospital. In leprosy hospitals one sees rows of patients with foot ulcers resulting from anaesthesia of their feet secondary to posterior tibial nerve damage. Worldwide about 20% of leprosy patients have nerve damage at the time of presentation. Unfortunately, in Britain diagnosis is delayed and we have found that 80% of our new patients have evidence of nerve damage. It is vital that leprosy is excluded in patients from Asia or Africa with unexplained neuropathy as leprosy is one of the most treatable of neuropathies.   Thickened posterior auricular nerve in Type 1 reaction of leprosy

   

Other manifestations of leprosy

Eye damage is a serious problem in leprosy especially if you already have anaesthetic hands and feet. Damage to the zygomatic branch of the facial nerve results in inability to close the eyelid whilst damage to the ophthalmic branch of the trigeminal nerve causes anaesthesia of the cornea. This combination of corneal anaesthesia and inability to close the eyelid sets the scene for corneal ulceration. Hence in reality, patients may present with skin lesions, neuritis, inflammation of the nerves or secondary consequences of nerve damage such as ulcers and muscle weakness. Patients with a combination of skin lesions and nerve damage are frequently referred to rheumatologists. They may be misdiagnosed as having a vasculitis. We have also seen several patients with ulnar nerve lesions who were referred to orthopaedic surgeons where the diagnosis of leprosy is rarely considered.

 

Differential diagnosis

At the tuberculoid end of the spectrum, leprosy lesions can emulate fungal infections, eczema and vitiligo. Testing these lesions for anaesthesia is critical. Leprosy is the only condition that gives anaesthetic skin lesions. Lesions on the face may be difficult to diagnose since a rich supply of nerve endings means that lesions may retain some sensation. At the lepromatous end of the spectrum the presence of acid fast bacilli in skin smears differentiates leprosy nodules from tropical conditions such as onchocerciasis, Kaposi’s sarcoma and post kala-azar dermal leishmaniasis. Nerve thickening rarely occurs in other conditions, namely amyloid and in hereditary sensory motor neuropathy type III.

 

Treatment of leprosy

There are five main principles of treating leprosy patients:

1. Stop the infection with chemotherapy.

2. Treat reactions.

3. Educate the patient about leprosy.

4. Prevent disability.

5. Support the patient socially and psychologically.

1. Chemotherapy

There are now effective short course regimens and the drugs do not need to be taken lifelong. For the purposes of treatment, patients are classified into either paucibacillary, i.e. smear negative or multibacillary, i.e. smear positive. Paucibacillary patients are treated for six months with a combination of rifampicin and dapsone. The rifampicin is given as a single 600 mg dose once a month. The dapsone is given daily. With multibacillary leprosy, patients receive a combination of monthly rifampicin 600 mg and clofazimine 300 mg and daily dapsone 100 mg and clofazimine 50 mg. With multibacillary leprosy the treatment is for two years or until smear negativity, whichever is sooner.

  

Drug side-effects are uncommon. As rifampicin is only given monthly it is unusual to get side effects and problems such as induction of liver enzymes. Occasionally patients will develop exfoliative dermatitis with dapsone. Clofazimine causes skin pigmentation which is reversible upon stopping the drug.

 

The relapse rate for paucibacillary leprosy is about 1% and for multibacillary about 0.77%. However, relapses occur 10-15 years after treatment so collecting data on relapse rates is difficult.  

 

2. Leprosy reactions

Leprosy reactions are due to immune mediated activity and cause much morbidity in leprosy. There are two types: 

a) Type I or reversal reactions

• Occur in borderline patients and are due to increased cell mediated immunity against Mycobacterium leprae and occur as a result of the upgrading of the immune system towards the organism. Unfortunately this upgrading whilst clearing out bacilli also causes local tissue destruction. Reactions are localised and occur as erythematous skin lesions and acute neuritis.

• The principle time is in the first two months after starting chemotherapy or during post-partum. Women are relatively immunosuppressed during pregnancy and after delivery their immune status improves. They then develop these damaging delayed type hypersensitivity reactions at sites of M. leprae antigens, in other words, skin and nerves. But reactions may also occur after the completion of treatment.

• Treatment: patients with type I reactions require high dose steroids for several months. You can start at 40 mg of prednisolone orally and then taper the steroids off over the next six months. It is very important to continue regular neurological assessment during this time.

  b) Secondly erythema nodosum leprosum (ENL)

• These reactions are due to immune complex deposition so they only occur in lepromatous leprosy and borderline lepromatous patients since one has to have a combination of antigen and antibody to form immune complexes. Patients with ENL have unpleasant systemic illness with fever, malaise and a development of tender subcutaneous nodules or plaques. They can also have lymphadenopathy, neuritis, bone pain, orchitis and acute iritis.

• Treatment: ENL reactions respond very well to thalidomide and this is the first line treatment in young men with ENL. Women with ENL are far more difficult to treat and I would usually try and manage their disease with short courses of high dose steroids first.

 
3. Patient education Patient education is vital. Leprosy remains a stigmatising disease wherever one lives in the world. Patients here in London are just as likely to conceal their diagnosis from their friends and family as patients in India. Employers frequently over react on hearing that a patient has leprosy. I usually start by asking them about their fears about leprosy. Many patients believe that it is a curse from God, a punishment for some misdemeanour. It is vital to reassure them that as soon as they have started effective antibiotic treatment they are no longer infectious. I also explain that it is safe for them to touch their family and friends, to share communal food and have sex with their partners. They are frequently worried about transmitting leprosy to their children. It is useful to emphasise that leprosy cannot be transmitted through skin to skin contact and that it is not hereditary. 

 

4. Prevention of disability This is a major undertaking and helping someone to protect their anaesthetic hands and feet is a life-long enterprise. It is really important to create patient self-awareness of the problems with anaesthetic hands and feet so that they can monitor themselves and prevent damage. I find it is very helpful to identify individually for each patient particular situations that may be risky for them. In the Indian population, women frequently do most of the cooking and are at risk of burning themselves. Men are frequently working as cooks or waiters in restaurants and need to alter their work pattern so that they are not picking up hot plates with their hands. Teenagers with anaesthetic feet damage their feet further through wearing high heels or walking too far.

It is vital to get patients to inspect their anaesthetic feet daily to look for any trauma and to ask themselves about the cause of trauma. They may also need to soak their feet daily and apply oil or emulsifying cream to keep the skin smooth and soft. Anaesthetic feet need appropriate shoes. Fortunately for many patients trainers will give them adequate protection and for many people these are more acceptable than orthopaedic shoes.

 

5. Other considerations I feel that women with leprosy are in double jeopardy. Not only may they develop post-partum reactions, they are at particular risk of social ostracisation and rejection, particularly by spouses and in-laws. There is no good evidence for relapse or increased presentation of new disease during pregnancy. However, women are at risk of post-partum reversal reactions. There were fears that HIV would cause increased cases of leprosy with unusual presentations. In the event this has not happened. HIV does not seem to predispose people to leprosy. However, patients with HIV may be at greater risk of developing reactions.