Causes and Treatment of Indeterminate Leprosy – A Study

 

Dr. Archana Singh

Assistant Professor, Department of Zoology, National P.G. College, Lucknow, Uttar Pradesh, India

*Corresponding Author E-mail: arvindsingh.luck@gmail.com

 

Abstract:

Leprosy is one of the oldest human bacterial disease recognized by a Norwegian scientist Armauer Hansen working in Bergen in 1873. Leprosy is still one of the infectious diseases and major health problem of developing countries. Leprosy is not a single entity but rather a spectral disease with varied clinico-pathological presentations. It is generally agreed that multibacillary cases (lapromatous and borderline lepromatous cases) are the most infectious for the community. This study has been taken to show the symptoms of leprosy and detection and management of indeterminate cases of leprosy

 

KEY WORDS: Leprosy, Indeterminate, Inflammatory Cells.

 

INTRODUCTION:

Leprosy is caused by Mycobacterium leprae. M. leprae is pleomorphic, straight or slightly curved, rod shaped gram positive bacteria.It is strong acid fast bacilli and occur in the human host intracellularly. In India, leprosy is known since ancient times as kustha roga and attributed to punishment or curse from God. There are about 1.3 million cases of leprosy in the world. More than 60% of world leprosy patients remain in India (Noordeen, 1995). It is still one of the major public health problems. For eradication of this dreaded disease the Govt. of India in 1955 had launched a campaign against leprosy known as the National Leprosy Programme. There are many species of Mycobacterium which affect directly and indirectly to man and animals. Mycobacteria which are pathogenic to man are Mycobacterium leprae and Mycobacterium tuberculae. M. leprae caused leprosy but M. tuberculae caused tuberculosis. Mycobacterium lepraemurium causes leprosy in rats.

 

OBJECTIVES OF THE STUDY AND METHODOLOGY:

1.     Overview of leprosy and its symptoms

2.     Early detection and management of indeterminate cases.

 

The preventive health hygiene and socio-economic status of society of developing countries has not well improved so this disease is still prevalent in the community. Early detection and treatment can be beneficial for the check and progress of the disease in the community so we planned to tackle the disease in very early stage. Indeterminate stage is the earliest stage so it is very easier to treat this disease at this stage. Present research work will be helpful in differentiating the indeterminate (Idt) cases from other paucibacillary cases and the work will help in confirming an early cases to be ‘leprosy’ or ‘not leprosy’.

 

Forms of Leprosy:

·       Leprosy afflictions go through phases. The greater part of the population having contact with patients with multibacillary forms of leprosy may be infected. The defense (immune status) in most cases will limit and arrest the multiplication of leprosy bacilli before signs of the disease appear.

·       The earliest recognized form of the disease is indeterminate (Idt) leprosy. This is an early unstable form in which majority of the patients will control the infections leading to spontaneous healing without treatment .

·       Some patients with indeterminate leprosy will progress to more persisting disease with a spectrum from paucibacillary tuberculoid leprosy to multibacillary lepromatous leprosy.

·       The last form is the most infectious and has the longest incubation period. Generally leprosy has a long and variable incubation period, and average of 3 to 5 years or more as long as 30 years for lepromatous cases. The tuberculoid leprosy have a relatively shorter incubation period.

 

Table 1: Classification of Indian Association of Leprologists

Number

Clinical Forms

(i)

Indeterminate (Idt)

(ii)

Tuberculoid (T)

(iii)

Borderline (B)

(iv)

Lepromatous (L)

(v)

Pure Neuritic (PN)

 

(i)        Indeterminate type: This denotes those early cases with one or two vague hypopigmented macules and definite sensory impairment. The lesions are bacteriologically negative.

(ii)      Tuberculoid type: This type denotes those early cases with one or two well defined lesions, which may be flat or raised, hypopigmented or erythematous and are anaesthetic. The lesions are bacteriologically negative.

(iii)    Borderline type: This type denotes those cases with four or more lesions which may be flat or raised, well or ill-defined hypopigmented or erythematous and show sensory impairment or loss. It may be bacteriologically positive. Without treatment, it usually progresses to lepromatous type.

(iv)     Lepromatous type: This type denotes those cases with diffuse infiltration or numerous flat or raised, poorly defined, shiny, smooth, symmetrically distributed lesions. These lesions are bacteriologically positive.

(v)      Pure neuritic type: This type denotes those cases of leprosy which show nerve involvement but do not have any lesions in the skin. These cases are bacteriologically negative.

 

TYPE OF INFLAMMATORY CELLS IN LEPROSY GRANULOMAS:

(i)        Lymphocytes: These are made in bone marrow, in spleen and in lymph nodes. They circulate in blood stream. They are small cells with dark staining nuclei and very little cytoplasm. Lymphocytes are responsible for cell mediated immunity and are present in large numbers in indeterminate and tuberculoid forms of leprosy.

(ii)      Plasma Cells: Plasma cells are like lymphocytes but they have more cytoplasm. They produce antibodies which circulate in blood stream and usually found in lepromatous granuloma.

(iii)    Foam Cells: In lepromatous leprosy the macrophages engulfs the bacilli which multiply inside the cell in large numbers, fat accumulates in the cell cytoplasm and vacuoles are formed; therefore, the presence of large intracellular vacuoles gives the foamy appearance. They are also called "lepra cells" or "Virchow cells".

(iv)     Macrophages: They produce in the bone marrow and are found in the blood as mococytes. They are also called histiocytes and reticulo-endothelial cells. The main function of macrophages in phagocytosis. These cells in case of lepromatous leprosy patients become foam cells in tuberculoid patients are converted into epitheloid cells.

(v)      Epitheloid Cells: The macrophages which have ingested M. leprae and having digested them are converted into epitheloid cells. They have vasicular nuclei abundant cytoplasm with indefiniate cell outline. Mostly found in tuberculoid leprosy.

(vi)     Giant Cells: These giant cells derived by the fusion of epitheloid cells also called Langhan's giant cells. They have many nuclei and vary in size and shape. These cells are found in tuberculoid leprosy.

 

 

Figure 1: Evolution of Leprosy Lesions (Yawalkar, 1974)

 

INDETERMINATE LEPROSY:

Indeterminate leprosy is a diagnostic problem both for the clinician and the pathologist. The clinical picture is vague and histopathological changes are non-specific. It is proposed to diagnose the patients with Ldt. leprosy using:

 

·       Clinical criteria, e.g. single, hypo-pigmented or erythematous macules with vague margins and sensory impairment (Charles et al., 1997).

·       Histopathological criteria, e.g. normal epidermis with preserved rete pegs, dermi-containing scattered areas of mononuclear cell collections around skin adnexal structures, and nerve endings. These may also be focal areas of epidermal erosion and spongiosis

·       In indeterminate leprosy acid-fast bacilli (AFB) are not always detected (Charles et al., 1997). According to Ridley (1971), Neyer (1972) and Parichha (1990), both lymphocytes and histocytes were present in inflammatory infiltrate, proliferation of spindle cells in superficial dermis rersembled with fibrocytes but had been proved to be phagocytes in established cases. Schwann cell proliferation might also be present. Histocytes and lymphocytes were also present around hair follicles, arrector pilorum muscles and sweat glands. Lesions are usually bacteriologically negative but may be positive.

 

CLINICAL MANIFESTATIONS:

Leprosy have broad spectrum of symptom. The clinical lesions, ranging from a small solitary hazy macule to widespread multiple shiny nodules. Indeed the manifestations of leprosy are so varied and divergent that it is hard to believe that they are caused by one and the same micro-organism.

 

This can be summarised as follows when a person is exposed to infection if there is:

(i)        Natural resistance                      No disease

(ii)      High resistance                           Localised disease (Idt, tuberculoid)

(iii)    Moderate resistance                   Disease fairly localized (Borderline, tuberculosis).

(iv)     Moderate resistance                   Mid. Borderline Unstable group

(v)      Low resistance                            Fairly wide spread (Borderline lepromatous)

(vi)     No resistance                              Wide spread disease (Lepromatous

 

(a)     Cardinal Signs of Leprosy:

The diagnosis of leprosy can be made if one or more of the following cardinal signs of disease are present:

1.     Loss of sensation

2.     Enlargement of nerve

3.     Presence of acid fast bacilli in skin smears

 

(b)     Clinical Examination:

Diagnosis of leprosy can be made after observing the various clinical features .

Appearance

Macule/Papule/Annular/Punched out lesions/ Diffuse infiltration/nodules      

Colour

Hypopigmented/Erythematous lesions

Number

Few (1 of 3)/more than three, less then ten/many numerous

Margin

Well defined/ill defined/slopping abrupt/ infiltrated/pebbled appearance.

Distribution

Asymmetrical/Symmetrical

Surface

Dry, scaly, smooth, shiny, central healing

Any tendency to spread

Presence of satellite lesion

Sensation

Not affected/diminished, absent

Hair growth

Not affected, markedly, affected, absent

AFB in skin smear

Nil, scanty, moderate numbers numerous

 

It is considered to be the earliest manifestation of the disease. Indeterminate leprosy presents as single or multiple, asymmetrical, slightly hypopigmented (pale) or faintly erythematous and usually ill-defined (hazy) macules on the skin. Sensation on the affected area is normal or slightly impaired, while sweating and hair growth are usually unaffected. The peripheral nerves are normal. Slit-skin smears are mostly negative (Leiker et al, 1983). However, careful examination of well-stained serial sections usually reveal acid-fast bacilli in dermal nerve fibrils infiltrated with lymphocytes (Browne, 1984). The lepromin test may be either negative or positive. Indeterminate leprosy is usually self-limiting or self-healing, but may progress to other forms of leprosy (ie. tuberculoid, borderline tuberculoid, midbordderline, borderline lepromatous or lepromatous leprosy).

 

Table 2: Clinical Manifestation of Indeterminate Leprosy

Skin lesions

Features

Appearance

Macule

Colour

Hypopigmented/erythematous

Number

One to three

Margin

Vague

Surface

Normal

Sensation

No impairment or slight impairment

Distribution

Asymmetrical

Size

Variable

AFB in skin smear

Nil may be 1+

Nerve and merve trunks

Not affected

Lepromin test

Variable

 

a)    Clinical Examination for Leprosy:

After taking the patient’s care history regarding the complaints, past treatment, duration family contact with leprosy and his/her work etc. suspected hazy areas must be viewed in a good light. Indeterminate leprosy in a dark skin is hypopigmented, sensory loss is present in the majority of leprosy patients and often occurs in the following order (Yawalkar, 1974).

 

Temperature šLight Touch š Pain and Pressure

·       Sensory deficit in the patches should be determined by touching the skin lightly with a wisp of cotton wool, a feather or the tip of a ball point pen. Touch the skin and ask the patient where he feels the touch. As the acuity of sensation varies from one part of the body to another the skin of contralateral side should be examined for comparison.

·       Heat sensation is tested with two test tubes – one containing hot water and the other cold, and pain sensation is tested by pin-prick. Because of the rich nerve supply to the skin of the face, sensory changes may be relatively less evident there than in other areas of the body (Binford, 1982).

·       The diagnosis of paucibacillary leprosy depends on these simple procedures. The presense of few, well demarcated chronic skin lesions associated with anaesthesis have suggested paucibacillary leprosy.

 

TREATMENT:

Leprosy patients should be treated with patience, perserverance and understanding. Besides the medical treatment, the leprosy patients needs moral support and reassurance so that he can gain self-confidence and self-respect.

 

(a)  Chemotherapy:

Until 1941 there was no really effective anti-leprosy drug, since hydro carpus (Chaulmoogra) oil which had been used in India and China for centuries was of little value. Sulfones, introduced in 1941 (Faget, et al., 1943), remained the mainstay of the chemotherapy for leprosy until around 1973 when primary sulfone resistance became a major concern (Pettit, 1964 and Pearson, 1981). Multidrug therapy (MDT), introduced in 1973 (Depasquale, 1975; Freerksen, 1975 and Waters, 1993), proved highly effective and greatly reduced the numbers of registered patients.

 

i)      Dapsone (4,4’ – diaminodiphenyl sulphone, DDS):

This is the most important and cheapest drug in the treatment of leprosy. It was synthesized by Fromm and Wittman in Germany, 1908. In 1947, Lowe tried dapsone orally in Nigeria (Bryceson, 1990). Clinical improvement is usually seen within 3 to 6 months of starting treatment. Depending on the body weight, adult patients should therefore receive a daily dose of 50-100 mg dapsone (1-2 mg/kg body weight) (Report of a WHO Study Group, 1982). During lepra reaction dapsone treatment should not be reduced (Report of a WHO Study Group, 1983). Primary resistance, was first observed in the 1970s (Pearson et al., 1977) and rates as high as 40% have been reported (Shepard, 1982). Side effects in patients with leprosy are rare. It may occasionally lead to malaise, weakness, haemolytic anaemia, leucopenia, fixed drug eruptions. Haemolysis of red blood cells is the most common of the adverse effects. It is uncommon except in very old or young patients or in patients will glucose-6-phosphate dehydrogenase (G-6-PD) deficiency (Beeching and Ellis, 1982 and Lancet, 1981).

 

 

Figure 2:- The structural formula of dapsone

 

ii)    Rifampicin:

This is a semi-synthetic derivative of a fermentation product of Streptomyces mediterranci, with an estimated minimum inhibitory concentration (MIC) of 0.3 g/ml (Rees et al., 1979). Rifampicin acts by inhibiting bacterial ribonucleic acid (RNA) synthesis. A single dose as low as 600 mg will kill the great majority (about 99.9%) of leprosy bacilli within a few days, so rendering the patients with multibacillary leprosy non-infectious (Browne S.G., 1984). Viable M. leprae can be detected in certain sites in lepromatous patients and treated with rifampicin daily for two to five years (Rees R.J.W. et al., 1979). Rifampicin should be given at least half an hour before food.

 

 

Figure 3: The structural formula of Rifampicin

Empiricla Formula : C43H58N4O12

Chemical Name: 3-(4-methl-1-piperazinyl iminomethyl)-rifampicin SV

 

The first time treatment of leprosy patients with rifampicin were published in 1970 (Rees et al., 1970 and Leiker, 1970). The most common side effect of rifampicin is red colouration of urine due to the excretion of the drug. It may also cause skin rashes, gastrointestinal syndrome, drowsiness, weakness and dizziness, Rifampicin is to be taken on an empty stomach.

 

iii)  Clofazimine (Lamprene, B663):

Clofazimine is a iminophenazine bright-red dye. It was developed as an anti-tuberculosis drug but proved to be of little value for such infections in human patients. It was first used for the treatment of leprosy in the early 1960s (Browne and Hogerzeil, 1962).

 

It interacts with mycobacterial DNA. It does not show cross-resistance with dapsone or rifampicin. Although this drug has been on the market since 1969, one case of Clofazimine-resistant leprosy has so far been reported in 1982 (Warndorff-Van Diepen, 1982).

 

Clofazimine is the only anti-leprosy drug possessing an anti inflammatory effect (Browne et al., 1981 and Waters, 1969). It may be useful in controlling reversal reactions in border line leprosy (Hastings et al., 1976). Clofazimine-mediated, anti-inflammatory and immunosuppressive activity may be due to its stimulating effect on the synthesis of anti-inflammatory and immunosuppressive prostaglandin E2 by human polymorphonuclear leucocytes, monocytes and macrophages in response to pro-inflammatory stimuli (Anderson R, 1985).

 

 

Figure 4: Structural formula of Clofazimine

3-(p-chloro-anilino)-10(p-chlorophenyl)-2, 10-dihydro-2-(isoprophylimino)-phenazine (Clofazimine)

 

It is advisable to administer 50 mg clofazimine daily to adult patients with multibacillary leprosy. Its capsules should be taken with meals or with a glass of milk. For multibacillary cases the WHO study group on Leprosy recommends a once monthly supervised dose of 300 mg Clofazimine in addition to the daily dose of 50 mg (WHO, 1982) (Table 10).

Moreover, its side effects are less dangerous than those of prednisolone (Warren G., 1976). In general, its dosages not greater than 100 mg daily (WHO, 1982). Daily doses exceeding 100 mg should be given for as short a period as possible (<3 months) and only under supervision (Yawalkar, 1988).

 

Table 3: Multidrug chemotherapeutic regimens for adult patients recommended by the WHO Study Group on Leprosy

Type of leprosy

Paucibacillary (Idt, TT, BT) Leprosy

Multibacillary (BB, BL, LL) Leprosy

BI according to the Ridley Scale

Less than two at all sites

Two or more at any site

Regimen

Daily (taken at home)

Dapsome 100 mg

Daily (taken at home)

Dapsome 100 mg

(100 mg every other day if 50 mg every other day if 50 mg capsules are not available).

Once a month (taken under supervision) Rifampician 600 mg

Once a month (taken under supervision)

Rifampician 600 mg

Clofazimine 300 mg

Duration of treatment

Six months

At least two years, preferably until negative skin smears are obtained

For proper implementation of MDT, careful bacteriological examination of skin smears is essential.

 

FINDINGS AND CONCLUSION:

A prospective case control study was carried out with the aim to study the suspected cases and to confirm the diagnosis of indeterminate leprosy in clinically diagnosed patients. The suspected subjects taken from the skin outpatients Department (OPD) of Gandhi memorial and associated hospitals, Department of Medicine at King George’s Medical College, Lucknow.

 

Study of leprosy is very fascinating to immunologist, interested in understanding the basic mechanisms involved in immune- deviation, tolerance and immunological enhancement.

 

The most interesting finding can be clinical examination which can be the detected through neural involvement. The nerve involvement shows that indeterminate patients goes towards paucibacillary or multibacillary leprosy. Indeterminate form is the initial stage of leprosy which may either progress towards any of the polar form and ldt leprosy can change towards paucibacillary or multibacillary leprosy.

 

It was concluded that correct diagnosis of indeterminate leprosy from other leprosy groups of spectrum could be made if results of clinical, histopathological, bacteriological and immunological were interpreted together. Detection of antibody levels appeared to be useful in the diagnosis and to confirm the indeterminate leprosy from other groups of spectrum. The early diagnosis and treatment of leprosy at indeterminate stage should be beneficial to reduce and to eradicate the leprosy from the community.

 

 

 

 

 

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Received on 28.03.2019       Modified on 17.04.2019

Accepted on 30.04.2019      ©A and V Publications All right reserved

Research J. Science and Tech. 2019; 11(2):122-128.

DOI: 10.5958/2349-2988.2019.00019.6