Leprosy

 

Salient features

 

·        Definition: A chronic infectious disease caused by the bacillus Mycobacterium leprae, an intracytoplasmic parasite of macrophages and Schwann cells; slowly progressive condition characterized by granulomas and neurotropism

·        Involvement: Primarily the skin and nerves, but causing sequelae to a wide range of tissues and systems including eyes, upper respiratory tract, lymphoid tissue, testicles, muscles, and bones.

·        Incidence: 214,783 new cases detected worldwide in 2016, essentially unchanged for the last 4 years. More than 80% of all new cases are detected in only 3 countries—India, Brazil, and Indonesia.

·        A clinical challenge: The long incubation time prior to the slow development of diverse symptoms (3-7 years post infection), the very low rate of disease progression in infected individuals, and issues with misdiagnosis all create challenges to the development of ways to interrupt transmission.

·        An immunologic spectrum of disease: Based upon the clinicopathologic findings, which reflect the degree/type of immunity, leprosy is divided into two major forms – lepromatous with a predominantly Th2 response and tuberculoid with a predominantly Th1 response

·        Diagnosis: Based on clinical signs and symptoms, hallmarks include loss of sensation within skin lesions, nerve swelling or pain, or demonstration of acid-fast bacilli in skin smears or biopsies. In lepromatous leprosy, multiple organisms are present in the dermis, whereas in tuberculoid leprosy, there are only a few organisms

·        Long-term morbidity: Despite the global use of multidrug therapy in use since the mid-1980s, up to 30% to 50% of all leprosy patients will experience some type of reactional episode that may result in a permanent neurologic deficit or disability.

 

 

Introduction

 

Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae with many clinical manifestations, which affect mainly the skin, the peripheral nerves, mucosa of the upper respiratory tract, and the eyes. It is divided into two major forms that depend upon the degree and type of immunity – lepromatous with a predominantly Th2 response and tuberculoid with a predominantly Th1 response. Leprosy is a serious health issue in a number of low-income countries. Although it seldom kills, leprosy represents a deforming, disabling, and stigmatizing disease. Once worldwide in distribution, leprosy is now seen primarily in tropical and subtropical regions of Asia, Africa, and Central and South America. The geographic distribution is probably related more to a lower standard of living and poorer hygiene than to a warmer climate. Early diagnosis and prompt therapy are key components in the strategy to control this chronic infectious disease.

 

History

Leprosy has afflicted humanity since time immemorial and it has left behind a terrifying image in history and human memory-of mutilation, rejection and exclusion from society. The earliest records of a ‘leprosy like’ disease came from Egypt, dating back as 1400 BC. The first historic mention of Leprosy in India dates back as 600 B.C., where it is denoted by a Sanskrit term ‘Kushtha’, literally meaning ‘eating away’ and patients were treated with ‘chaulmoogra’ oil at that time. The term Kushtha is still used today in India and many other countries in South East Asia. Clay statues of leprosy patients were also found in Mesopotamia dates back as 400 BC.

 Mycobacterium leprae was discovered by Hansen in Norway in 1873 and, it is the oldest known bacterium pathogenic to man.

 

 

Prevalence of leprosy

 

The global case-load of leprosy has reduced by almost 90% over the last 20 years. Over 15 million cases have been detected and cured worldwide. 214,783 new cases detected worldwide in 2016, essentially unchanged for the last 4 years. More than 80% of all new cases are detected in only 3 countries—India, Brazil, and Indonesia. The goal of the World Health Organization (WHO) is a prevalence rate of <1 case per 10 000 persons, which has been achieved in all but a few countries.

India has a low prevalence of leprosy except in 3 states/union territories and these are Bihar, Chhattisgarh and Dadra and Nagar Haveli.

 

Epidemiology

 

Although men and women are equally affected, lepromatous Leprosy is more common in men than women by a 2:1 ratio. Leprosy affects all races and ages; however, its peak incidence occurs in individuals between 10–15 and 30–60 years of age.

The disease has a very long incubation period, but the average incubation period is between 3 to 5 years. Leprosy is an infectious disease directly transmitted from man to man after a prolonged close contact of susceptible person to an open case of leprosy. About 95% of the exposed population is not susceptible (resistant) to the disease; of the remaining 5%,  larger part successfully eliminates M. laprae through an effective immune response while only a small fraction (1%) having specific impairment to cell mediated immunity (CMI) to M. leprae develop clinical disease.

 

 

Mode of transmission

 

Three requirements for the spread of leprosy are: a contagious patient, a susceptible person, and close or intimate contact. In endemic countries, the vast majority of new cases are in children and young adults who have close relatives with contagious forms of the disease.

 

The principal means of transmission is by (droplet infection) aerosol spread from infected nasal secretions of untreated lepromatous leprosy patients, when they sneeze or blow nose, to exposed nasal mucosa of susceptible person via inhalation. Every 1cc of nasal secretion contains 1-2 millions of lepra bacilli.

 

 

 

 

Up to 80% of people exposed to M. lepre may solve the problem and get rid of the bacilli before appearance of symptoms or after subclinical leprosy. Some patients will develop primary neural leprosy, with no skin lesions. All those with skin lesions pass through an indeterminate form, and then evolve to polar tuberculoid leprosy (TT) or lepromatous leprosy (LL) disease or to an unstable borderline form of leprosy. The pauci-bacillary (PB) pole toward TT has a good cellular immune response (CIR), with the presence of Th1 cytokines, while multibacillary pole toward LL present an impaired CIR and a high antibody response, with Th2 cytokines. Acid-fast bacilli and anti-PGL-IgM are both, low or negative on PB and increase through multi-bacillary pole. Reversal reaction may happen especially in border leprosy, whereas erythema nodosum leprosum occurs in borderline-lepromatous leprosy (BL) and LL patients. Chronic neuritis or neuropathy may happen in primary neural leprosy and in all but the indeterminate clinical leprosy form.

 

 

Etiology

M. leprae is an acid fast, non-cultivable, slightly curved rod shaped and gram positive bacteria. It is an obligate intracellular micro-organism, a parasite that lives within cells, particularly macrophages and Schwann cells. It grows best at temperature (30 degree) below the core body temperature of humans and this explains the localization of leprosy lesion to cooler areas of the body (e.g. nose, testicles, ear lobes) as well as regions where the peripheral nerves are close to the skin; sparing the warmer areas such as midline back, hairy scalp and intertriginous regions (axilla, groin and perineum). It has a doubling time of 12 days.

As the majority of the exposed individuals do not develop the disease, thereby genetic susceptibility and type of leprosy appear to correlate with specific HLA types. Individual with HLA-DR2 and HLA-DR3 are more likely to develop tuberculoid form and those with HLA-DQ1 the lepromatous form.

Leprosy is the most common treatable cause of neuropathy in the world. In all patients with leprosy, the nerve tissue is involved. The dermal nerves are infected in all skin lesions, including those due to indeterminate leprosy of childhood.

 

 

Classification of leprosy

 

(a) Ridley and Joplin classification:

 

 

Based on clinical, bacteriological, histological and immunological features of the patients, Ridley’s has classified the disease into five groups, ranging from high to low resistance: polar tuberculoid (TT), borderline tuberculoid (BT), mid borderline (BB), borderline lepromatous (BL) and finally polar lepromatous leprosy (LLp). TT and LLp are clinically and immunologically stable, but between the poles, they are unstable and can move upward or downward. It should be noted that the term lepromatous leprosy (LL) includes both sub polar lepromatous (LLs) and polar lepromatous (LLp). There is existence of an inderminate phase (IL) also.

 

(b) Clinical classification:

 

In 1997, the WHO classified leprosy for therapeutic purpose in endemic areas based on the number of skin lesions where no laboratory facilities are available into: 1. Single lesion Paucibacillary (SLPB) leprosy (one skin lesion only); 2.Paucibacillary disease (IL, TT and BT) has 2 to 5 skin lesions; and 3.Multibacillary (MB) disease having more than 5 skin lesions (BB, BL and LL). This simplified classification is based solely on the number of cutaneous lesions, independent of their size, location or histologic features.

Any patient showing a positive skin smear, irrespective of the clinical classification should be treated for MB leprosy.

 

 

Early lesion and its natural course

The initial skin lesion consist of one or more slightly hypo pigmented or erythematous macules, with ill-defined border (hazy), most commonly found on the face, extensor surface of the limbs, buttocks or trunk except the warmer regions. Hair growth and nerve function are unimpaired. This early and transitory stage of the disease is called indeterminate leprosy and found in persons (especially children) whose immunological status is yet to be determined. The indeterminate phase may last for months or years before resolving spontaneously if CMI is good, but about 25% progress to one of the determinate types of leprosy such as lepromatous, tuberculoid or borderline if CMI is weak.

Indeterminate macules cannot be felt by the examining finger; therefore, once the border becomes palpable the lesion is no longer indeterminate.

 

 

Immunology of leprosy

 

This reflects the underlying host immunity as measured by the T-lymphocyte and antibody responses to Mycobacterium leprae. Spontaneous and drug-induced fluctuations in the immune response are responsible for type 1 and type 2 reactions. TT, tuberculoid leprosy; BT, borderline tuberculoid leprosy; BB, mid-borderline leprosy; BL, borderline lepromatous leprosy; LL, lepromatous leprosy; IFN, interferon; IL, interleukin.

 

 

The cell mediate immune response to M. leprae not only determines whether disease will develop, but also which type of leprosy. Both T cells and Macrophages play important role in the processing, recognition and response to M. leprae antigen. In TT, strong CMI response clears antigen at the expense of local tissue destruction and is characterized by few lesions, rare organism, highly organized epitheloid cell granuloma and a tendency to self-cure. LL patients are unable to mount a CMI response to M. leprae and is characterized by widespread lesions, abundant AFB, disorganized granoloma with foamy macrophages and if untreated relentless progression. A sharp margin on a plaque is the inscription of anti M. leprae DTH on the skin and nerve trunk palsy is the inscription on a peripheral nerve.

 

In tuberculoid skin lesion, CD4 cells predominate (CD4/CD8=2:1) and produce Type 1(Th1) proinflammatory cytokines profile such as INF gamma and IL-2 whereas in lepromatous skin lesion, CD8 cells predominate (CD4/CD8=1:2) and produce Type 2(Th2) anti-inflammatory cytokines profile such as IL4 and IL10. The presence of Type 1 cytokines likely results in strong T cells and macrophage activation, the result being CMI to localize the infection. On the other hand, the Type 2 cytokines found in lepromatoous lesion likely lead to strong antibody response, but concomitantly inhibit T cell and macrophage response, resulting in progression of the infection. The decision by the host as which cytokine profile to make, that is, Type 1 or Type 2 may depend upon the response of the innate immune system to M. leprae. In tuberculoid leprosy, Toll like receptors of the innate immune system are activated by the mycobacterial lipoproteins, causing the release of IL12, a key inducer of Type 1cytokine response. In lepromatous leprosy, PGL1 suppresses the T cell response and thereby reduces gamma IFN production.

 

Tuberculoid type:

INF-Y:

1.  mobilizes macrophages → stimulates phagolysosome formation

2.  stimulates production of iNOS → generates free radicals → helps in killing the bacteria

3.  stimulates macrophages → recruits monocytes → differentiates into epithelioid macrophages → granulomatous inflammation

 

Lepromatous type:

1.  T-H2 response → IL-4, 5 and 10 → suppress macrophage activation in response to M.leprae

2.  Macrophages also produce lower levels of IL-1.

3.  antibodies may be formed against M.leprae antigens leading to immune complex formation: Erythema nodosum, Vasculitis and Glomerulonephritis 

 

 

Pathogenesis and clinical aspects of leprosy:

 

The bacilli after entering the nose by inhalation multiply on the inferior turbinate and have a brief bacteremic phase and via the endoneural blood vessels it enters the peripheral nerves. The outer layer of the bacterial cell wall contains phenolic glycolipid 1(PGL-1) and entry into the nerves is mediated by the binding of species-specific trisaccharide present in PGL-1 to the G domain of the alpha-chain of laminin 2 (found only in peripheral nerves) in the basal lamina of Schwann cells, proving a rational for why M. lapre is the only bacterium known to invade peripheral nerves. Once the bacilli have been engulfed by the Schwann cells, their subsequent fate and the type of leprosy which ensues, depends on the resistance of the individual towards the infecting organism.  Resistance is highest in tuberculoid leprosy (TT), diminishes through the borderline spectrum, and is lowest in lepromatous leprosy.

 

 

Diagrammatic representation of a cross-section of a peripheral nerve.

 

Nerves invaded by leprosy bacilli are peripheral nerves which are closed to the skin, either dermal (cutaneous) nerves or nerve trunks situated superficially, in regions that are relatively cooler (face & limbs).

 

 

 

 

Mechanisms of damage in leprosy, and tissues affected. 

Mechanisms under the broken line are characteristic of disease near the lepromatous end of the spectrum, those under the solid line of the tuberculoid end. They overlap in the center where, in addition, instability predisposes to type 1 reactions.

Tuberculoid leprosy (TT)

 

Bacilli which enter Schwann cells slowly multiply within them and the bacilli which are liberated by rupturing Schwann cell enter neighboring Schwann cells and thus the intraneural infection spreads, but a stage is reached when the intraneural infection is ‘recognized’ by the immunological system and the nerve is invaded by lymphocytes and histiocytes (macrophages), which kill the bacilli and the macrophages become fixed epithelioid cells, and groups of these become giant cells. Thus, the tuberculoid granuloma is formed within the nerve causing nerve destruction and this in turn results in pain and swelling of the affected nerve followed by anesthesia and/or muscle weakness and wasting, depending on the type of nerve involved.

Pain in the affected nerve may be the earlier symptom of nerve involvement, possibly in the absence of signs of nerve dysfunction, for it must be remembered that about 30 % of the sensory fibers must be destroyed before evidence of sensory impairment can be detected. If the body’s defense mechanism (cell-mediated immunity) is capable of anchoring the infection within one or more nerves, without skin involvement, a pure neural tuberculoid leprosy results. But if bacilli or their antigens escape from the nerve into surrounding skin, they are phagocytized by upper dermal macrophages, and a well-organized tuberculoid granuloma is formed in the skin (a skin lesion is likely to develop at that site), which are elongated and generally run parallel to the surface surrounding neurovascular elements, each focus consisting of epitheloid cells at the center with a surrounding zone of lymphocytes; giant cells are sometimes present among the epithelioid cells. Some of these foci invade the sub epidermal papillary zone – the zone which is always free in lepromatous and borderline leprosy – and may even erode the basal layer of the epidermis. Bacilli are not seen. Cutaneous nerves within the tuberculoid foci appear greatly swollen by epithelioid cells granuloma and get destroyed. Often only a few fascicles of the nerve are infiltrated but inflammation within the epineurium causes compression and destruction of unmyelinated sensory and autonomic fibers. Myelinated motor fibers are the last to get affected producing motor impairment. Severe inflammation may result in caseous necrosis within the nerve.

As CMI is strongly expressed in tuberculoid leprosy, bacillary multiplication is restricted to one or a few skin sites and peripheral nerves, so only nerves and skin show clinical evidence of disease. A skin lesion of tuberculoid leprosy is usually single but there may be two or even three. The typical lesion is an erythematous plaque, with raised and clear-cut edges sloping towards a flattened and hypo pigmented center. Dark skins may not show the erythema. The surface is anesthetic, anhidrotic and hairless, and sometimes scaly. (Impaired sensation is difficult to demonstrate in a lesion on the face because of the generous supply of sensory nerve endings).

 

Less commonly the lesion is a macule, erythematous in light skins and hypo pigmented (never depigmented) in dark skins and the surface is anesthetic, anhidrotic and hairless.

 

The skin lesions may be anywhere on the body apart from the warmer areas.

 

If the examiner runs a finger around the lesion, whether it is a plaque or a macule, a thickened sensory nerve may be palpated just beyond the outer edge or a thickened nerve trunk may be felt in the vicinity, e.g. a thickened ulnar nerve if the lesion is near the elbow.

 

Skin smears are negative. There is often spontaneous remission of the lesions in about 3 years, or remission may be sooner with treatment.

 

Lepromatous leprosy (LL)

 

Because of depressed cell-mediated immunity, bacilli which enter Schwann cells multiply unchecked; they also enter perineurial cells to multiply within them, and there is infiltration of the perineurium with histiocytes and plasma cells giving the perineurium a ‘’onion-peel’ appearance with subsequent perineurial damage which is slow to progress in contrast to the pathological nerve damage in the other types of leprosy. The bacilli which are liberated by the rupture of Schwann cells and perineurial cells are engulfed by macrophages which, instead of destroying them and becoming fixed epithelioid cells (as they do in TT), become wandering macrophages.  Bacilli multiply inside these macrophages and travel to other tissues, through blood, lymph and tissue fluid mainly to the cool, superficial tissues including anterior chamber of eyes, upper respiratory mucosa, testes, small muscles and bones of hands, feet and face, as well as peripheral nerves and skin.

 

These swollen macrophages, packed with bacilli, are known as lepra (syn. Virchow) cells, and the masses of bacilli which accumulate in their cytoplasm are called globi when seen in skin smears or biopsies.

 

Because of the absence of activated lymphocytes and macrophages the nerve damage is slow and gradual in onset, so physical signs in the skin and nasal mucosa are likely to be noticed by the patient before signs of nerve damage are noticed, hence pure neural lepromatous leprosy has never been described. Once bacilli are liberated into the skin from the nerve by the rupture of overstretched lepra cells, they are picked up by fresh histiocytes and carry their bacterial load to other skin areas or to distant tissues. In the skin, they form the typical diffuse leproma consisting of foamy macrophages (lepra cells) and a few lymphocytes and plasma cells lying in the deeper dermis with a free papillary sub epidermal zone with thinning of the epidermis and flattening of rete ridges. Bacilli within the macrophages are fragmented and granular and due to accumulation of mycobacterial phospholipids as cytoplasmic droplets and they give a foamy appearance. Hanks have calculated that the number of bacilli varies between 1 and 7 billion per Cm3 of infiltrated skin in a lepromatous subject.

 

There are two symptoms which can alert the early diagnosis of lepromatous leprosy, and which may precede the skin lesions by months or years; these are nasal symptoms and edema of legs and ankles. Nasal symptoms consist of stuffiness, crust formation, and blood-stained discharge. Nasal scraping, or nasal mucus (nose-below), will reveal large numbers of bacilli; incidentally, a skin smear taken from apparently normal skin, will also positive at this time.  Edema of legs and ankles, always bilateral, is likely to be noticed towards the end of the day, disappearing after a night’s rest; only in the late stages is it persistent, and the legs become wooden hard on palpation. Edema is due to a combination of gravity and increased capillary stasis and permeability, and the latter is probably due to a combination of leprous involvement of capillary endothelium and damage to autonomic fibers within dermal nerves controlling capillaries.           

 

Skin lesions of LL consist of macules, papules, and nodules, or with all three, but macules are likely to appear first. Skin lesions are multiple and have a bilateral and symmetrical distribution involving the face, limbs, buttocks and trunk except the warmer regions of the body. Hair growth and sensation are not initially impaired over the lesions.

 

Macules in lepromatous leprosy are erythematous or hypo pigmented, and are small, numerous, have a shiny surface and vague edges. Papules and nodules usually have normal skin color but sometimes are erythematous. When a patient presents with all three types of skin lesions it will usually be found that the grosser lesions, such as papules and nodules are on the face and limbs, while macular lesions are on the trunk.

In polar LL, there is also diffuse infiltration and gradual thickening of the dermis which results in nodules on face over the brows, nose, ear lobes and chin and the nose becomes swollen and broadened.

 As the untreated disease advances, thickening of the skin of forehead causes deepening of the natural lines (leonine facies), ear lobes become thickened and elongated ( Budha ear), eyebrows and eyelashes become thinned and lost (superciliary and ciliary madarosis respectively), the nose may collapse due to septal perforation and loss of anterior nasal spine (Saddle nose deformity), the voice becomes hoarse, the upper incisor teeth fall out. The skin of the legs becomes ichthyotic and thickened; ulcers may form on the legs when nodules break down, and a slow fibrosis of peripheral nerves results in nerve thickening and bilateral insensitivity of the limbs, known as ‘glove and stocking’ anesthesia leading to shortening of fingers and toes due to painless repeated trauma.

 

The presence of large numbers of leprosy bacilli in peripheral nerves leads to fibrosis which very slowly destroys those which have the greatest concentration of the bacilli, i.e. those which have a superficial course where they are cool, thus applying particularly to limbs. Unfortunately, this slowly developing fibrosis is likely to occur even if the patient has taken anti leprosy drugs regularly, for leprosy bacilli can be found, albeit in granular form, within peripheral nerves long after they have disappeared from the skin of the treated patients. In fact, this fibrosis is a reaction to the presence of dead (granular) bacilli rather than to living ones, for there is no nerve fibrosis in the early stages of the disease when the nerves contain healthy, solid staining bacilli.

 

Evidence of damage to nerves occurs late in lepromatous leprosy and therefore skin manifestations are always present when neurological signs and symptoms occur. Patient presents with bilateral and symmetrical polyneuritis in late stage of the disease due to slow fibrosis of peripheral nerves that result in nerve thickening and its associated sensory and/or motor loss depending upon the type of nerve involved.

 

In LL, the thickening of peripheral nerves (which is always symmetrical) occur in the late stages (in spite of treatment), for there is no nerve thickening in the early stages, whereas in TT and borderline leprosy nerve thickening (which is always asymmetrical) occurs early and slowly subsides as treatment is continued over the years.

 

 

Nerve examination sites

 

 

Thickened nerves feel firm and smooth, thickening being localized to the portions of nerves which are most superficial (and therefore coolest) e.g. supraorbital nerve (above the eyebrows), the great auricular nerves in the neck (winds around sternocleidomastoid), the supraclavicular nerves as they cross the clavicles, the ulnar nerves just above the elbows (olecranon fossa), the radial cutaneous and median nerves at the wrists, the lateral popliteal (common peroneal) nerves as they wind round the necks of fibulae, the sural nerves at the back of the legs, the posterior tibial nerves behind the medial malleoli, and the superficial peroneal nerves in front of the ankles and on the dorsa of the feet. Due to fibrosis of the type C peripheral sensory fibers there is bilateral and symmetrical glove and stocking anesthesia(S-GPSI). The longest peripheral sensory nerve fibers are first affected causing numbness and anesthesia, which begins on the dorsum of the hands and feet, progresses to the  extensor surface of the forearms and the legs and finally over the trunk. Sensation of palms and soles is retained until late in the disease.

The limbs are tested for sensory impairment-the first symptom is usually inability to distinguish hot and cold sensation followed by perception of light touch, then that of pain and lastly loss of sense of deep pressure. (Order of loss of sensation: Temperature > Light touch > Pain > Deep pressure).Anesthetic skin is particularly liable to blister when exposed to heat, due to the fact that reflex dilatation of skin capillaries is impaired because of damage to dermal nerves.

Peripheral nerve trunks are vulnerable to damage at sites where they are superficial or are in fibro-osseous tunnels with signs and symptoms of inflammation or without such overt manifestation (silent neuropathy), causes both dermatomal sensory loss and muscle dysfunction supplied by that peripheral nerve. Posterior tibial nerve is the most frequently affected nerve followed by ulnar, median, lateral popliteal and facial nerve. Damage to motor nerves results in muscle weakness, followed by wasting and paralysis. Muscles typically affected are those supplied by the facial nerve (facial palsy), ulnar nerve (claw hand), median nerve (ape hand), both ulnar and median nerves (complete clawing), lateral popliteal nerve (dropped foot), and the posterior tibial nerve (claw toes or hammer toes). When the ulnar nerve is damaged, the earliest sign is difficulty in approximating the little finger to the ring finger when the fingers are outstretched due to weakness of small muscles of the hand, and anesthesia of the medial half of the hand; when the lateral popliteal nerve is damaged, the earliest sign is weakness in holding the big toe in a dorsiflexed position against light pressure and anesthesia of outer border of the foot and posterior tibial nerve damage causes paralysis of the small muscles of the foot and anesthesia of the sole.

When borderline leprosy downgrades to lepromatous leprosy, the resultant LLs can be differentiated from LLp by the presence of both typical lepromatous and borderline skin lesion, and also several asymmetrical thickened nerves.

Enormous numbers of leprosy bacilli are found in skin smears and nasal scrapings, mostly in globi, and moderate numbers in apparently healthy skin.

Tuberculoid vs. lepromatous leprosy

 

 

In addition to skin and nerves the following tissues may be involved in lepromatous leprosy:

1.   Nails of fingers and toes

These may appear dry, lusterless, shrunken, narrowed with longitudinal ridges. The relevant digits become narrowed distally because of bone atrophy. With advanced boned absorption and atrophy the shortened digits retain the nail in much shrunken form.  

 

2.   Mouth, pharynx and larynx

Papules may appear on mucosal surface of lips, and nodules are found on tongue, palate and uvula and laryngeal mucosa. Nodules on the palate and laryngeal mucosa may ulcerate causing perforation of the hard palate and hoarseness of voice respectively.

 

3.   Eyes

 

Eye damage results from both nerve damage and bacillary invasion. The anterior structures of the eyes (the cooler portions) such as cornea and the iris are commonly involved, in the form of keratitis and insidious  iritis where the patient has no ocular discomfort or redness, and if the condition is undiagnosed and untreated there is increasing iris atrophy and eventual blindness. Acute iritis, presenting with red and painful eyes, occurs as one of the manifestations of lepra reaction. Damage to the facial nerve (7^th cranial nerve) or trigeminal nerve (5^th cranial nerve) occurs in their course outside the skull (where they are most cool). When the facial nerve (7^th cranial nerve) is damaged, the earliest sign is patient unable to approximate the lower eyelid to the upper lid ( called lagophthalmos)  by asking the patient to close his eyes slowly and gently, likewise, when both lids are involved, the lower one shows higher degree of paralysis. This differentiates leprous facial palsy from Bell’s palsy. This Lagophthalmos results from paresis of the orbicularis oculi due to selective involvement of the zygomatic and temporal branches of the facial (VIIth) nerve. Facial lesions cause a 10-fold increase in the risk of facial nerve damage. Damage to the ophthalmic branch of the trigeminal (5^th) nerve leads to anesthesia of the cornea and conjunctiva, which results in drying of the cornea, a reduction in blinking, and leaves the cornea at risk of minor trauma and ulceration. The corneal reflex should be tested with a wisp of cotton wool; absence of the reflex is indicative of damage to the trigeminal nerve (5^th cranial nerve). When lagophthalmos is associated with corneal anesthesia, exposure keratitis may develop, and if neglected blindness ensues. In LL such neural changes occur late in the course of the disease and are usually bilateral, whereas in the borderline and tuberculoid types they occur early and in association with skin lesions on the face, particularly during lepra reaction.

 

 

4.   Bones

 

In hands and feet all the phalanges undergo slow atrophy and absorption, and then disappear causing shortening of the affected fingers and toes; metacarpals and carpal bones are spared. But in the feet, the distal end of the metatarsals become thin and pointed – an appearance known as ‘penciling’ or the sucked candy stick’. Tarsal bone disintegration causes foot deformity.

 

The shortened fingers are characteristic of lepromatous patients because their hands insensitive for years before they become weak and therefore they are used in daily work, whereas in non-lepromatous patients both anesthesia and muscle weakness tend to occur together with rapid paralysis of intrinsic muscles; therefore the affected hand is not used.

 

In the skull, there is atrophy of the anterior nasal spine causes nasal collapse and atrophy of the maxillary alveolar process causes loss of the upper central incisor or all four upper incisors teeth, and these two skull changes known as ‘facies leprosa’

 

 

5.   Testes

 

Testicular atrophy occurs in late stage of the disease or if there is repeated attacks of acute epididymo-orchitis during lepra reactions which causes impotence, sterility and gynecomastia.

 

 

Skin smears or biopsies from any part of the skin are full of leprosy bacilli.

 

It is important to note that combination of skin and neural disorder is strongly indicative of leprosy, and the correct diagnosis can usually be made with the help of a pin, if fails to demonstrate any sensory impairment, a smear can be made with the scalpel and M. leprae may be found after suitable staining.

 

There are two special manifestations of lepromatous leprosy:

 

Histoid leproma

 

Patient presents with firm, skin colored, shiny, glistening nodules, which appear on the skin of patients whose disease is relapsing because of inadequate treatment. Histologically histoid nodules contain spindle-shaped histiocytes and that the bacilli within them are longer than normal.

 

Lucio leprosy

 

This term applies to the diffuse non-nodular type of leprosy. The patients first notice impairment of sensation in hands and feet and this is followed by gradual loss of eyebrows, eyelashes and body hair and at the same time the whole body becomes diffusely thickened, rendering it stiff and smooth as in scleroderma. There is swelling of hands and feet, widespread small telengiectases, perforation of nasal septum, thickening of upper eyelids gives the patients a sleepy look, laryngeal involvement may cause hoarseness of voice and ichthyosis is a late development. However, unlike LL, skin nodules are absent, and the eyes are not damaged.

 

Borderline leprosy (BT, BB and BL)

 

Nerves are attacked in the same way as described for TT. The cellular response is less focal and less destructive, and epithelioid cells are found adjacent to areas of bacillated Schwann cells. Bacilli are found within affected nerves, in small numbers at tuberculoid end and large numbers at the lepromatous end. Borderline leprosy occurs in those whose degree of resistance lies between tuberculoid and lepromatous pole, so their clinical features vary according to the position in the spectrum. Damage to structures other than skin and nerves will not be manifest clinically in borderline leprosy, even though bacilli may be present in other tissue. Borderline leprosy is the most common type of leprosy seen, with BT predominating. They are immunologically unstable and tendency to move in either direction along the borderline spectrum, ‘down-grades’ towards lepromatous, especially if untreated, or ‘upgrades’ towards tuberculoid if treated.

 

In borderline leprosy there is a prolonged polyneuritic phase before the appearance of skin lesions where several peripheral nerve trunks are thickened asymmetrically and non-functioning (the nerves are grossly thickened in TT, less so in Borderline).

 

Skin lesions are intermediate in number between those of the two polar types, depending on the position of the patient on the borderline spectrum, and are distributed asymmetrically. Skin lesions are macules, plaques, annular and punched out lesions distributed asymmetrically, of which annular and punched out lesions are characteristics of the middle of the spectrum and all shows some degree of sensory loss but not complete anesthesia as in TT. Towards the tuberculoid end of the spectrum, lesions are fewer and drier, have more hair loss and anhidrosis, are more anesthetic and have edges which are better defined, and have fewer bacilli in smears and biopsies, and vice versa towards the lepromatous pole.

 

 

 

Clinical features of leprosy Clinical findings LL BL BB BT TT I Type of lesions Macules, papules, nodules, diffuse infiltration Macules, papules, plaques, infiltration Plaques and dome-shaped, punched-out lesions Infiltrated plaques Macule/ Infiltrated plaques, often hypopigmented Macules, often hypopigmented Number of lesions Numerous Many Many Single, usually with satellite lesions, to more than 5 One or few (up to 5) One or few Distribution Symmetric Tendency to symmetry Evident asymmetry Asymmetric Localized, asymmetric Variable Definition Vague, difficult to distinguish normal versus affected skin Less well-defined borders Less well-defined borders Well-defined, sharp borders Well-defined, sharp borders Not always defined Sensation Not affected Diminished Diminished Absent Absent Impaired Bacilli in skin lesions Many (globi) Many Many Few (1+), if any, detected None detected Usually none detected LL, lepromatous leprosy; BL, borderline LL; BB, mid-borderline leprosy; BT, borderline TT; TT, tuberculoid leprosy; I, indeterminate.

 

Nerve involvement

 

Nerve injury is the hallmark of progressive leprosy infection and involves both myelinated and unmyelinated nerves. Biopsy specimens taken from affected nerves of leprosy patients reveal perineural and intraneural inflammation and, in myelinated fibers, eventual demyelination. Nerve damage occurs in two settings, in skin lesions and in peripheral nerve trunks. In skin lesions, the small dermal sensory and autonomic nerve fibers supplying dermal and subcutaneous structures are damaged, causing local sensory loss and loss of sweating within the area of the skin lesion.

 

Nerve involvement is responsible for the clinical findings of anesthesia within lesions of paucibacillary and borderline leprosy, and of a progressive “stocking-glove” peripheral neuropathy in lepromatous leprosy. Tuberculoid leprosy is characterized by asymmetrical nerve involvement localized to the skin lesions. Lepromatous nerve involvement is symmetrical and not associated with skin lesions. In TT, neural lesions are caused by the inflammatory infiltrate in the nerves, and these lesions occur early in the disease. In the LL, neural lesions are caused by massive bacillary infiltration of the nerves with compression and eventual fibrosis and occur later in the disease.

 

 

Complications of Leprosy

1) Motor deficit (In order of frequency): Clawing of toes (Posterior tibial nerve), Claw hand (ulnar nerve), Ape hand (median nerve), Foot drop (Common peroneal nerve), Facial palsy (facial nerve)

2) Anesthetic deformities:

Anesthesia → Injury → Neglect → Infection → Loss/Damage of tissue → healing with deformity

 

Sequelae of leprosy

 

 

 

 

 

Pregnancy and Leprosy

_______________________________________________________

 

Effects of pregnancy on the woman with leprosy

Pregnant women have decreased cell-mediated immunity and thus have an increased risk of acquiring the infection. 

• If the disease is incubating, pregnancy can result in overt expression.
• Pregnant women also have an increased incidence of type I reactions .In borderline leprosy upgrading (reversal) reaction is most likely to occur during the puerperium when there is a rapid regaining of CMI which was depressed during pregnancy. During pregnancy, downgrading reaction may occur because of decreased CMI, and is most likely to be manifested in the 3^rd trimester.
• Type II reactions are possible throughout pregnancy and lactation, and they are associated with earlier loss of nerve function.
• Ideally, pregnancy should be avoided until leprosy is well controlled.

 

Effects on the infant

 

·       Babies born of leprosy mothers weigh less and grow more slowly and have a high risk of contracting leprosy from the mother if she has untreated LL.

 

Leprosy Reaction (Reactional States)

 

Leprosy reactions are episodes of sudden increase in the activity of the disease due to alteration in the immunological status of the patient and are part of the natural course of the disease. These are characterized by acute inflammation that appears suddenly. Reactions are often due to complication of treatment, but they may occur before treatment is started or after it has been completed and are divided into two types: type 1 and type 2 reaction.

 

TWO MAJOR TYPES OF LEPROSY REACTIONAL STATES
	Type 1 – reversal reaction with “upgrading”	Type 2 – vasculitis (most commonly erythema nodosum leprosum)
Immune mechanism	Enhancement of cell-mediated immunity with a Th1 cytokine pattern	Excessive humoral immunity with a Th2 cytokine pattern and formation of immune complexes; may be accompanied by increased cell-mediated immunity
Pathogenic process	Delayed-type hypersensitivity reaction	Cutaneous and systemic small vessel vasculitis
Leprosy category	Borderline (BT, BB, BL) or tuberculoid with immunologic recovery during or after treatment	Lepromatous and BL > BB; especially patients with a high bacterial index who are undergoing treatment
Clinical characteristics	·       Increased inflammation in established skin lesions   ·       Emergence of “new” skin lesions   ·       Acute nerve pain or tenderness (neuritis) and loss of function   ·       Recent (<6 month history) or progressive neurologic impairment in the absence of painful nerves	·       Nodular skin lesions   ·       Fever, myalgias, malaise   ·       Severe joint swelling and pain   ·       Iridocyclitis   ·       Lymphadenitis   ·       Hepatosplenomegaly   ·       Orchitis   ·       Glomerulonephritis
Treatment	Prednisone	Thalidomide

 

 

 

Type 1 lepra reaction

 

This is delayed Type IV hypersensitivity reaction and is associated with a rapid change in cell-mediated immunity (CMI). It is typically seen in borderline patients and occasionally in LLs because of their immunological instability, and if the reaction is associated with a rapid increase in specific CMI due to treatment, we speak of upgrading or reversal reaction (RR) and if the reaction is associated with a reduction in immunity in the absence of treatment, we speak of downgrading reaction. The various shifts across the leprosy spectrums in upgrading reactions are LLs→BL→BB→BT→TTs.  LLp and TTp, the polar forms, immunologically stable. The reverse holds good in downgrading reactions: BT→BB→BL→LLs.

 

The patient may present with one or more of the following features:

·       The most prominent sign is increase inflammation of some or all the existing skin lesions; they become more reddish and swollen. Lesions desquamate as they subside.

·       Painful, tender and swollen peripheral nerves with signs of nerve damage-loss of sensation with or without muscle weakness. Facial palsy is most likely to occur if there is a lesion on one cheek.

·       Edema of hands, feet, or face

·       Rarely, New lesions may appear

 

Type 2 lepra reaction

 

This type of reaction is not associated with alteration in CMI as it is an immune complex vasculitis (cutaneus and systemic) mediated by Type III hypersensitivity reaction and thus is a humeral antibody response. It occurs almost exclusively in lepromatous leprosy (LLp and LLs), only occasionally in BL. It presents with various presentations, including the classical erythema nodosum leprosum and Lucio's phenomenon.

 

Risk factors

 

The risk factors for developing ENL include LL type and a high-bacillary index, bacillary index of 6.

Age and gender are not risk factors for ENL, as has been corroborated in various studies. Pregnancy and lactation are proven precipitating factors for ENL, with a significantly higher incidence in pregnant and lactating females. Minimal evidence implicating psychological stress, puberty, intercurrent infection, vaccination, HIV, malaria, and tuberculosis as triggering factors has been found but is not yet sufficient to be conclusive.
ENL is found to be highest during the first year of MDT in most studies, although a few studies claim the incidence to be highest in the second and third years after starting MDT.

Multiple episodes of ENL are seen in 39% to 77%.  There are five risk factors for multiple episodes of ENL. They are an LL subtype, a smear >4+, more than five nerves enlarged, the presence of skin nodules or infiltration.

The main features are:

 

·       The classical ENL consists of  multiple crops of painful, tender, multiple brightly red raised evanescent (lasting only 2 or 3 days, rarely longer), nodules and plaques arising on clinically normal skin, tend to be distributed bilaterally and symmetrically on the on the extensor surface of the limbs or the face. In fact, they may appear on any skin area except the warmer regions of skin, which are avoided by leprosy lesions as well as by ENL. They desquamate as they subside.

·       The old-standing leprosy lesions do not undergo any clinical change, and ENL lesions do not superimposed on them.

·       In severe reaction, nodules may become suppurate or blisters and break down to form ulcers (erythema necroticans)

·       Bacilli in ENL lesions are not as numerous as in the patient’s leprosy lesions, and are mostly fragmented and granular.

·       Edema of face, hands and feet.

 

The onset of ENL may be of the cutaneous, rheumatoid, or mixed types. The rheumatoid type presents with symmetrical arthritis affecting the small joints of the hands and feet, in the so-called “rheumatoid distribution. This has an incidence of more than 57%. The cutaneous onset is characterized by the classical skin lesions which precede systemic involvement.

Neuritis although more common and more severe in type 1 reaction, may also occur in ENL. It presents as painful, enlarged nerves, with or without accompanying functional impairment. It is imperative to diagnose neuritis early to prevent permanent loss of function.

 

ENL is a systemic disorder producing fever and malaise and may be accompanied by neuritis, myositis, arthritis, iritis (iridocyclitis), dactylitis, lymphadenitis, epididymo-orchitis, and glomerulonephritis.

 

Arthritis in ENL is usually acute in onset, involving the small joints of the hands and feet, along with the knees and elbows. Arthritis lasts for a few weeks, and in most cases, resolves completely with treatment.

The natural course of untreated ENL is of 1 to 2 weeks but the reaction may be recurrent and may last up to many months.

ENL may be classified as acute, recurrent or chronic, as follows:

Acute ENL is defined as a single episode lasting less than 24 weeks.

Recurrent ENL is characterized by repeated episodes of ENL occurring after 28 days of stopping treatment for ENL.

Chronic ENL is defined as ENL occurring for 24 weeks or more, wherein a patient has required continuous treatment, or any treatment-free period has been 27 days or less.

 

Lucio phenomenon

 

Lucio phenomenon although designated as type III lepra reaction is usually considered a variant of type II lepra reaction. It is an ulceronecrotic reaction occurring in a diffuse, non-nodular form of leprosy known as Lucio leprosy. Features are crops of hemorrhagic infarct that evolves to bullous lesions, rapidly breaks down to produce deep painful ulcers especially below the knee and finally develops a crust which falls off a few days to leave a superficial atrophic scar.

 

It has been classically described in Mexico by Lucio and Alvarado but a few cases have also been reported from India.

 

Diagnosis

The diagnosis of ENL is predominantly clinical. Naafs et al. proposed their criteria to diagnose a type II (ENL) reaction: 

 

Naafs criteria: A patient is considered to have a type II reaction if he has the major criterion or at least three minor criteria:

 

 

The Ryrie test is performed by stroking a blunt instrument like the handle of a reflex hammer over the sole with light pressure (as in the Babinski reflex test). The test is positive if the patient expresses pain by wincing. The Ellis test is performed by squeezing the forearm of the patient just above the wrist gently with both hands. As in the Ryrie test, it is considered positive if the patient's wincing face indicates pain. However, these tests are now obsolete and of historical significance only.

Laboratory tests show low hemoglobin, raised total count and hematocrit. Deranged liver function tests and C-reactive protein may also be seen.

On histopathological examination, neutrophils within the granulomas are considered the hallmark of ENL. There is an intense neutrophilic perivascular infiltrate in the dermis and subcutis. However, this is not a rule, and many cases of ENL present without this classical neutrophilic infiltrate. Other histopathological features seen include leukocytoclasia, dermal edema, neutrophilic panniculitis, fibrin in vessel walls, and granulomas and folliculotropism.

The smears obtained from fine-needle aspiration from the enlarged lymph nodes and stained with Papaniculaou, May-grunwald-Giemsa (MGG) stain, and modified ZN stain showed cellular smears with a good number of foamy macrophages interspersed with reactive lymphoid cells with plenty of neutrophils in the background. Modified ZN stained smears showed foamy histiocytes containing lepra bacilli.

 

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Table

Diagnosis of leprosy

 

The diagnosis is usually made clinically on the basis of two out of three characteristic findings, or by the demonstration of AFB in slit-skin smears, or by histology typical of leprosy. The cardinal signs are:

1. Anesthesia of a skin lesion, or in the distribution of a peripheral nerve or over dorsal surface of hands and feet,

2. Thickened nerves, especially at the sites of predilection

3. Typical skin lesions.

 

Ø Sensory deficit in a skin lesion is diagnostic of leprosy

 

Diagnostic Tests

 

(1) Skin smears

 

Ideally all patients should have one examination before starting treatment. The main purpose for this is to prevent any MB cases being treated with PB regimen. The AFB load of a patient is determined by modified Ziehl–Neelsen staining of slit‐skin smears. Suspect lesions, and sites commonly affected in LL, should be sampled (e.g. the forehead, earlobes, chin, extensor surface of the forearm, buttocks and trunk).  In stained smear a search is made for red rods (against a blue background) at 100× with oil immersion and the bacilli can be seen lying singly, in clumps, or in compact masses within macrophages; these are known as globi. Living bacilli appear as uniformly stained rods (solid –staining) and dead bacilli appear irregularly stained (fragmented bacilli) or as granules (granular bacilli)).

 

The number of bacilli seen in an average oil-immersion microscopic field is known as the bacteriological index (BI) and includes both living and dead bacilli. Slit-skin smears only detect bacilli present at a concentration greater than 10(4)/gm tissue. If lepra bacilli are seen after searching 100 fields, report the result as positive and as negative if no bacilli are found.

 

In virtually all TT patients, and in most BT cases, acid-fast bacilli (AFB) cannot be found, whereas in BB, BL, LL, bacilli are demonstrable with ease in slit and skin smears.

 

With treatment bacilli disappears from BB lesions in a few months, from BL lesions in a year or two and from LL lesions it may take 6-10 years.

 

The morphological index (MI) is the percentage of solid-stained bacilli, calculated after examining 200 red-staining elements lying singly, and this index will tell if a patient’s leprosy is active or not and give valuable information as to response to treatment. With treatment MI will gradually fall and increases without treatment.

 

The lesion is cleaned with ether or alcohol, and a fold is gripped firmly between thumb and forefinger to render it blood free. An incision 5 mm long and 3 mm deep is made with a small‐bladed scalpel (size 15); the blade is turned at right angles to the cut, and without relaxing finger pressure, the wound is scraped several times in one direction. Fluid and pulp from the dermis, collected on one side of the blade, are gently smeared on to a glass slide. A bloody smear is useless. The smear is then fixed over a flame and stained.

 

(2)Skin biopsy

 

This is helpful in diagnosis and classification of leprosy. A biopsy specimen in leprosy must include the full depth of the dermis together with a portion of subcutaneous fat otherwise leprosy changes in the deeper layers of the dermis will be missed.

 

(3)Nerve biopsy

 

This essential in a pure neural leprosy where there is no skin lesion and will show typical tuberculoid or borderline histology  as the case may be, together with bacilli in most borderline case. A thickened purely sensory nerve is suitable, such as radial cutaneus nerve at the wrist, superficial peroneal nerve on the dorsum of the foot or the sural nerve at the back of the leg as they do not contain motor fibers and therefore there is no risk of motor damage.

 

(4)Lepromin test

 

Lepromin is a heat killed bacilli from a lepromatous nodule or infected armadillo liver. Lepromin 0.1 ml, is injected intradermally and the reaction is read at 48hr (Fernandaz reactin) or 4 weeks (Midsuda reaction). The Fernandaz reaction indicates delayed hypersensitivity to the bacillary antigen and the Midsuda reaction is a more reliable index of CMI. The lepromin test is a non-specific test of occasional value in classifying a case of leprosy. It is strongly positive in TT, weakly positive BT, negative in BB, BL and LL and unpredictable in indeterminate leprosy.  Neither test is diagnostic, since both may be positive in healthy people with no evidence of leprosy.

 

(5)PCR test

 

PCR is a very sensitive and specific method for the detection of very small numbers of M. leprae DNA in slit skin smears.

By PCR, a number of genes encoding antigenic proteins (e.g. 36 kD aproline-rich antigen, Ag85B) can be amplified, as can M. leprae-specific repetitive repeat sequences (RLEP region). This molecular technique is of particular help in paucibacillary leprosy and can be performed on slit-skin smears and fresh, frozen, or paraffin-embedded skin biopsy specimens. In a study utilizing RLEP real-time PCR, M. leprae DNA was detected in 38 (75%) of 51 paraffin-embedded skin biopsy specimens from patients with paucibacillary leprosy. In addition, immunohistochemical staining of biopsy specimens for the PGL-1 antigen may prove helpful in paucibacillary disease.

 

(6)Serological tests

 

Serologic assays for anti-PGL antibodies are only sensitive for the diagnosis of leprosy in the setting of untreated multibacillary disease. However, measurement of these antibodies can help to classify patients, monitor the response to treatment, and predict leprosy reactions. Serum levels of anti-PGL-1 IgG and IgM antibodies are highest in those with lepromatous disease and lowest (or absent) in those with BT or tuberculous disease, therefore representing a marker of mycobacterial “load”. Elevation of anti-PGL-1 IgM antibody levels is also associated with reactions and impairment of nerve function.

 

TREATMENT

 

There are five main principles of treatment:

1. Stop the infection with chemotherapy

2. Treat reactions and reduce the risk of nerve damage

3. Educate the patient to cope with existing nerve damage, in particular anesthesia

4. Treat the complication of nerve damage

5. Rehabilate the patient socially and psychologically

 

 

MULTIDRUG THERAPY/WHO SCHEME FOR THE TREATMENT OF LEPROSY
	Rifampin	Clofazimine	Dapsone	Ofloxacin	Minocycline	Therapy duration
MB (>5 lesions*)	600 mg once monthly	300 mg once monthly and 50 mg daily	100 mg daily	−	−	12 blister packs over 12 to 18 months
PB (2–5 lesions*)	600 mg once monthly	−	100 mg daily	−	−	6 blister packs over 6 to 9 months
PB (single lesion*)	600 mg × 1	−	−	400 mg × 1	100 mg × 1	Single dose
Dose adjustments for children
10 to 14 years of age, MB†	450 mg once monthly	150 mg once monthly and 50 mg every other day	50 mg daily	−	−	12 blister packs over 12 to 18 months
<10 years of age, MB†	300 mg once monthly	100 mg once monthly and 50 mg twice weekly	25 mg daily	−	−	12 blister packs over 12 to 18 months
5 to 14 years of age, single lesion PB	300 mg × 1	−	−	200 mg × 1	50 mg × 1	Single dose

* WHO classification for endemic areas when no facilities for performing bacilloscopy are available.

† For PB disease (2–5 lesions), clofazimine is not required and the duration of therapy is 6 to 9 months.

 

Expectations of treatment

Antibacterial treatment for leprosy is highly effective, with low relapse rates, but needs to be taken over 6, 12 or 24 months. However, new patients can be reassured that their infection is curable and that the aim of treatment is to minimize further nerve damage. Patients should not develop the mutilating sequelae seen previously.

 

Left untreated, borderline patients will downgrade towards the lepromatous end of the spectrum, and lepromatous patients will suffer the consequences of bacillary invasion. Borderline patients are at risk of developing type 1 reactions, which may result in devastating nerve damage. Many patients present with established nerve damage, which cannot be reversed. Treatment of the neuritis is currently unsatisfactory, and some patients with active neuritis will develop permanent nerve damage despite treatment with corticosteroids. It is not possible to predict which patients will develop reactions or nerve damage. Nerve damage and its complications may be severely disabling, especially when all four limbs and both eyes are affected.

 

 

Chemotherapy

 

The problems of defaulting, drug resistance and bacterial persistence, have led the WHO Study Group to recommend MDT in the treatment of leprosy in 1982. The WHO-MDT regimens are robust, i.e. their efficacy is not impaired by minor irregularities in compliance.

 

In a multibacillary patients three distinguishable types of bacilli: fully drug sensitive bacteria, drug resistant mutants and a small proportion of persisters, dormant non multiplying bacilli. Treatment with multidrug regime should eliminate nearly all organisms. The drugs used in WHO-MDT are a combination of rifampicin, dapsone and clofazimine for MB patients and of rifampicin and dapsone for PB patients and single dose combination of rifampicin, ofloxacin and minocycline (ROM) for SLPB, in blister packs can be used. However, ROM is no longer supplied through the WHO, and most national programs do not endorse it. Among these, rifampicin is the most important drug and therefore is included in the treatment of all type of leprosy. The rational for recommending three drug regimens is that rifampicin will kill all susceptible organisms, including those resistant to dapsone, and dapsone will eventually eliminate all susceptible organisms, including those resistant to rifampicin. Clofazimine is added to obviate the risk of primary dapsone resistance.

 

In children <10 years of age the doses should be preferentially calculated according to the weight of the child: dapsone 2 mg/kg/day, rifampicin 10 mg/kg, and clofazimine 1 mg/kg/day daily and 6 mg/kg monthly. Fortunately, tolerance to standard antileprosy drugs is good in children. Available MDT blister packs though convenient are not child-friendly. Treatment dropout rates in children range from 10% to 20% in some programs, main cause being the child's refusal to cooperate in swallowing tablets. Child-friendly treatment options such as flavored syrups are a need of the hour for improvement in dosing and compliance.

 

 

Rifampicin is a potent bactericidal drug and it acts by inhibiting DNA-dependent RNA polymerase, thereby interfering with bacterial RNA synthesis. Four days after a single 600mg dose, bacilli from a previously untreated multibacillary patient are no longer viable. The drug should be given once a month in a single dose at least 30 min before breakfast to have its full effect. Toxic effects have rarely been reported in the case of monthly administration. Hepatotoxicity may occur with mild transient elevation of hepatic tranaminases, but and is not an indication for stopping treatment. The urine may be slightly reddish in color for a few hours after its intake. This should be explained to the patient after starting MDT.

 

Dapsone is weakly bactericidal, acts by blocking bacterial folic acid synthesis and is very safe in the dosage used in MDT. Side effects are very rare but the main one is allergic reaction, causing itchy skin rashes and exfoliative dermatitis. Therefore, patients known to be allergic to any of the sulfa drugs should not be given dapsone. Dapsone commonly causes mild haemolysis and should be suspected in any patient developing anemia while on treatment. A small minority of patients feels temporarily ‘woolly-headed’ and unable to think clearly an hour or two after taking the 100 mg tablet. This symptom improves by taking the tablet at bed time.

 

Clofazimine is weakly bactericidal. It has anti-inflammatory effect, which is useful in the management of ENL reactions. The most noticeable side effect is brownish-black   pigmentation of skin but although this disappears within 6-12 months after stopping the drug and it should be explained to patients before starting it. Clofazimine also produces a characteristic ichthyosis on the shins and forearms. Gastrointestinal side effects ranging from mild cramps to diarrhea and weight loss may occur as a result of clofazimine crystal deposition in the wall of small bowel.

 

Second line

 

Ofloxacin, minocycline and clarithromycin are established second line bactericidal drugs for M. leprae, and may replace dapsone and clofazimine.

 

Ofloxacin: this drug belongs to fluoroquinolone group of antibiotics. It has been found to be effective against leprosy in a dose of 400mg. Side effects are rare and mild in nature; these include GI complaints, headache and dizziness. The drug is not recommended for use in pregnant women and children below 5 years of age.

 

Minocycline: this drug belongs to tetracycline group of antibiotics. This drug has shown moderate activity against leprosy bacilli in a dose of 100mg. Most common side-effect reported is dizziness, which may last for few hours after taking the drug. The drug is not recommended for use in pregnant women and children below 5 years of age.

Clarithromycin, given in 500 mg daily doses to multibacillary patients, has a similar bactericidal effect.

A triple‐drug combination (rifampicin, ofloxacin and minocycline) which can be given as a single monthly dose for 6 or 12 months can be used to treat patients with adverse effects to one of the components of MDT.

 

Completion of treatment and cure

 

Any PB patient who has taken six doses of PB-MDT within 9 months and any MB patient who has taken 12 doses of MB-MDT within 18 months should be considered as cured. All such patients should be told about the early signs of reactions and relapses and to report any such events promptly.

 

It is important to remember that leprosy patients who have completed a full course of treatment should no longer be regarded as a case of leprosy, even if some sequelae of leprosy remain.

 

Patients with special needs

• Patients who do not tolerate MDT because of adverse reactions or contraindications
• These patients pose a difficult clinical problem and should be treated with other new antileprosy drugs. For patients who refuse to take clofazimine because of skin discoloration, explain that this will reverse within a few months after completion of treatment and encourage the patient to continue with clofazimine. In exceptional cases, ofloxacin 400 mg or minocycline 100 mg/d may be used under supervision in place of clofazimine.
• For adults with MB leprosy who do not tolerate rifampicin, clofazimine 50 mg/d with ofloxacin 400 mg and minocycline 100 mg for 6 months (intensive phase); followed by clofazimine 50 mg/d with ofloxacin 400 mg/day for at least an additional 18 months is recommended (maintenance phase).
• If the patient develops dapsone toxicity, dapsone may be substituted with clofazimine in PB at the same dose as used for MB patients, but for 6 months only. In patients with MB, dapsone should be stopped, and treatment should be continued with rifampicin and clofazimine at the standard doses.

 

·       Pregnancy

 

MDT is considered safe, both for the mothers and the child, and therefore should not be interrupted or curtailed during pregnancy.

 

·       Treatment of coexistent leprosy and tuberculosis

 

These patients require appropriate antituberculosis therapy in addition to the standard MDT. Rifampicin is common to both regimens and it must be given in the doses required for tuberculosis.

 

·       HIV infection

 

The management of leprosy patient infected with HIV is the same as that of any other patient with leprosy, including the treatment of reactions.

 

·       Relapse

 

A patient who has completed the full course of treatment may rarely develop new skin patches or nodules and /or new nerve damage, and may be suspected of having relapsed. Relapsed MB patients are should be given another course of MB-MDT regimen while PB patients should be retreated with PB-MDT-PB regimen, if their disease is still paucibacillary. But if they relapse with multibacillary disease then they should re-treated with MB-MDT regimen.

 

 

Points on MDT treatment

 

·       Every leprosy patient should receive treatment with more than one antileprosy drug

·       Standard MDT is very safe, effective and easily administered treatment regimen. After the first dose, the patient is no longer infectious to others, because the transmission of disease is interrupted

·       It is available free of charge for leprosy treatment in most centers

·       Standard MDT is for a fixed duration: 6 months (PB), 12 months (MB) and one dose ROM (SLPB)

·       At the completion of a full course of MDT, the patient is considered cured, as there are virtually no relapses. Bacilli may be found but they are not viable.

·       Use clinical criteria to classify and decide treatment regimen

·       If in doubt of classification, give MB treatment regimen

·       Active follow-up after completion of treatment is not necessary

·       In case of relapse, re-treat with appropriate MDT regimen

 

 

Management of lepra Reactions

 

Leprosy reactions are the major cause of nerve damage and disability in leprosy. Therefore these should be detected early and treated promptly. The occurrence of leprosy reactions does not mean that MDT drugs are not being helpful and therefore MDT should not be stopped during reaction. Treatment with MDT significantly reduces the frequency and severity of reactions. Possible occurrence of reactions need to be explained to the patients, otherwise patients could be misunderstood them as adverse effects due to drugs, or might think that the treatment they are getting is harming them.

 

 

Type 1 reaction

 

The diagnosis and treatment of reversal reaction is urgent because of the risk of permanent damage to the peripheral nerve trunks due to neuritis and such cases should be treated immediately with oral corticosteroids.

 

Steroids: indications and dose

 

Steroid treatment is indicated in the following circumstances:

• For moderately inflamed skin lesions and Type 1 reaction that is severe enough to cause skin ulceration or are uncontrolled by paracetamol or NSAIDs (such as ibuprofen);

• Neuritis, as shown by the emergence of new nerve function impairment.

 – Neuritis may accompany a Type 1 reaction, whether mild or severe;

– It may be associated with pain in one or more nerves;

 – The patient may complain of NFI, e.g. loss of sensation or muscle weakness;

– It may by silent, i.e. without clear symptoms.

 

Oral prednisolone is the steroid normally used. Clinical trials have usually included patients with Type 1 reaction and/or NFI. NFI lasting longer than six months does not respond to corticosteroid therapy; however, it can be difficult to establish the duration of NFI in clinical practice, particularly if the deterioration has been asymptomatic. When treating with prednisolone, the key parameters are the starting dose and the length of the course.  In general, the starting dose should be between 0.5 and 1.0 mg per kg of body weight per day. In most settings 0.5 mg/kg daily would be an appropriate starting dose for a first course, meaning 30 or 40 mg daily for most adults. Recent studies suggest that a course lasting 20 weeks gives the best results, starting at either 30 mg or 40 mg, depending on body weight. A longer course of prednisolone is more important than a high initial dose.

 

The best steroid regimen to treat reactions and neuritis continues to be debated, both in terms of dose and duration. Prolonging the course to 32 weeks provided little additional benefit. The currently recommended course of steroids, therefore, lasts for 20 weeks.

 

A suggested 20 weeks course of prednisolone for an adult patient is as follows:

 

40 mg od for first 2 weeks, then

30 mg od for weeks 3 and 4

25 mg od for weeks 5 -8

20 mg od for weeks 9- 12

10 mg od for weeks 13 -16 and

5 mg od for weeks 17 - 20.

 

Second-line drug used in the treatment of neuritis included cyclosporine. Cyclosporine could be a safe alternative for patients with neuritis who are not improving with prednisolone or are experiencing adverse events related to prednisolone.

 

Additionally, it is important to provide rest to the affected nerve until symptoms clear by applying a padded splint to immobilize the joint/s near the affected nerve. The aim is to maintain the limb and affected nerve in the resting position to reduce inflammation and prevent worsening of nerve damage.

 

If there is no nerve involvement, the reaction can be controlled by rest and analgesics (NSAIDs).

 

 

Type 2 reaction

 

For mild reactions, bed rest and analgesics (indomethacin, ibuprofen, diclofenac, acetaminophen, tramadol) are sufficient.

For neuritis, treatment is similar as described under reversal reaction.

 

Corticosteroids such as prednisolone offer rapid control, and are considered as the first line of treatment of severe ENL. They rapidly control inflammation and relieve pain. They are usually started at the lowest possible dose required to keep ENL under control, and then they are gradually tapered as per the course of the disease. Severe ENL is best treated initially with moderate doses of 30–40 mg prednisolone (for an adult) per day. Oral prednisolone is also required for erythema necroticans (vesicular or bullous ENL).

 

Recurrent and chronic ENL require increased or prolonged doses of steroids to control the inflammation and symptoms. Patients with chronic ENL may become dependent on steroids. Serious side effects of long steroid treatment course have been reported.

 

 

Prednisolone, thalidomide and clofazimine generally give better results than other treatments (such as NSAIDs and pentoxifylline).

 

The indications for using thalidomide or clofazimine as additional or second-line drugs are:

• Steroid non-responders: those requiring higher doses of steroids with each episode of ENL;

• Steroid dependence: those for whom tapering the steroid dose results in flares;

• Patients with a serious comorbidity.

 

 

Thalidomide: The use of thalidomide in ENL provides an effective alternative to steroid therapy. It provides a rapid anti-inflammatory effect by acting on TNF, which is a pro-inflammatory cytokine. Although thalidomide remains the treatment of choice for type 2 reactions, its use is limited by its teratogenic effects, cost, and poor availability. It is now recommended to only be administered to males and post-menopausal females. Thalidomide may initiate teratogenic effects when taken early in pregnancy. Women in the childbearing age group can be given thalidomide but only when being supervised in a prevention of pregnancy programme. This includes patients being seen every 28 days, having negative pregnancy tests and using two different methods of contraception, before receiving a prescription for thalidomide.

 

Kaur et al. showed that thalidomide gave better symptom control than prednisolone. Nabarro et al., 2016 showed that using thalidomide reduced dependence on prednisolone. Thalidomide is not useful in managing neuritis, which is less frequent in Type 2 as compared with Type 1 reactions. It is useful in managing the general malaise, fever and pain of severe ENL. The adult dose varies between 100 mg and 400 mg daily, in divided doses. A typical regimen used in India started with 300 mg per day in divided doses, tapering down to 100 mg daily over two to three weeks, depending on the response. A maintenance dose may be required in chronic cases, the dose being determined by the response.

 

There are recognized adverse events with thalidomide including sedation, peripheral neuropathy and venous thrombosis. Low-dose aspirin could be used to reduce the risk of thrombo-embolism.

 

Lenalidomide and pomalidomide are thalidomide analogues with different side-effect profiles (e.g. more myelosuppression) that could have potential utility in the treatment of type 2 reactions.  

 

 

Clofazimine: Clofazimine is a useful and inexpensive anti-inflammatory drug used in ENL. The dose required to control ENL is higher than the dose (50 mg daily) used in MDT.  When used at a dose of 300 mg/day, the serum concentration doubles. It exerts an anti-neutrophilic effect and inhibits prostaglandins. It has no effect on acute episodes but particularly useful in managing recurrent and chronic type II reactions, where its steroid-sparing effect comes into great use. The disadvantage is that it is very slow in action, and takes 4–6 weeks to exert its effects. It also produces significant gastrointestinal side effects and dark discoloration of the skin.

 

 A widely used regimen is as follows:

• 300 mg, daily, for 1 month;

• 200 mg, daily, for 3–6 months;

• 100 mg, daily, for as long as ENL symptoms remain.

 

 

The combination of pentoxyphylline 400mg twice daily and clofazimine 300mg /day can be used in ENL when a systemic steroid is contraindicated.

Azathioprine and methotrexate have been used along with prednisolone and as steroid-sparing agents in the treatment of ENL.

Cyclosporine A: although cyclosporine has been used for corticosteroid-resistant type 1 reactions, it was first used in ENL by Mshana in 1982, with good results in chronic steroid-dependent ENL which had failed to respond to thalidomide. Cyclosporine A provides a beneficial effect in ENL by increasing the number of T suppressor cells in lesions.

 

TNF-α inhibitors: TNF-α plays a key role in the pathogenesis of ENL,  which provides the rationale for use of TNF-α inhibitors in ENL. Infliximab is a human-murine chimeric monoclonal antibody against TNF-α, and etanercept is a dimeric fusion protein of the extracellular portion of the p75 TNF receptor coupled to IgG1. Both of these effectively reduce TNF-α level and have been found to have impressive clinical responses in ENL. The dangers are severe immunosuppression and increased risk of reactivation of latent tuberculosis infection (more so with infliximab as compared to etanercept).

Minocycline: A single study reports the use of minocycline in the treatment of ENL. Narang et al. report 10 cases of chronic or recurrent ENL who were treated with oral minocycline at a dose of 100 mg daily for 3 months, with gradual tapering of the prednisolone regimen to discontinuation. A good response was observed in 80% of the cases. Minocycline along with its antibacterial properties also exhibits good anti-inflammatory and antiapoptotic activity, which may explain its efficacy in ENL. It also inhibits microglial activation, which confers upon it a neuroprotective function. This may help in leprosy neuritis.

 

Another promising class of drugs is the phosphodiesterase-4 inhibitors with strong anti-inflammatory action, which prevent degradation of cyclic adenosine monophosphate, thereby decreasing the production of pro-inflammatory cytokines.  A single case report in 2019 reports the use of Apremilast in two cases of poorly controlled chronic ENL, with significant clinical improvement and no adverse events. An analogue of apremilast (roflumilast) is currently being studied in ENL patients, with promising initial results.

 

 

Summary

 

Steroids remain the drug of choice for both Type 1 and Type 2 reactions. They provide significant benefit, both in the relief of symptoms and in the restoration of nerve function. There are significant adverse events, however, especially when the course of steroids is prolonged, including a mortality risk. Every effort should be made to reduce steroid dependence through the use of so-called steroid-sparing drugs. At present, thalidomide is the most widely used steroid-sparing drug in leprosy, although it is only applicable to Type 2 reaction.

 

 

Acute iritis (iridocyclitis): 4 hourly Instillation of 1% hydrocortisone eye drops and 1% atropine drops twice daily.

 

Acute epididymo-orchitis: prompt treatment with prednisone and the scrotum should be supported by a suspensory bandage.

 

MDT is the choice for leprosy treatment. However, when there is intolerance to any of the drugs, available alternatives may be used, as ofloxacin, minocycline, or clarithromycin.

 

 

Complications of nerve damage and Patient Education

 

Complications of nerve damage, which are the major cause of deformity and disability in leprosy, are preventable by early diagnosis, prompt treatment and education of the patient. Monitoring sensation and muscle power in patient’s hands, feet and eyes should be part of routine follow up, so that new nerve damage is detected early.

 

Care of the hands and feet is a very important aspect of management, as the anesthetic hand or foot is repeatedly injured by the careless patient, and because of the absence of pain the injured limb is not rested and healing is therefore protracted and often complicated by secondary infection. Chronic plantar ulceration is a more important cause of morbidity than is leprosy itself, for it continues to be a problem long after the leprosy has been arrested – in fact, for the rest of the patient’s life.

The care of hands and feet involves the education of the patient on how to care for his limbs, the regular daily examination of hands and feet for minor injuries and the prompt treatment of any injuries found.

• Patients can avoid burns to the hand by wearing suitable gloves when cooking or attending to fires, by given up cigarette smoking or by using a cigarette holder, and by insulating the handles of all cooking utensils so that they do not conduct heat.

 Patients should be educated about proper self-care to ensure healthy feet.

(1)Patients should never use heating pads or hot water bottles, and they should not stand too close to a heater or fireplace as there is danger of insensitive feet and lower legs can be burned.

(2)To avoid plantar ulceration the patient must avoid all unnecessary standing and walking, all hurrying or running, must learn to take short steps and should soften the callosities which form under the heads of the metatarsals by soaking the feet in warm water daily for 10 – 15 minutes and then the callosities are rubbed with a pumice stone.

(3)Patients should be advised to cut their toenails straight across.

(4)For dry skin, use a moisturizing lotion that does not contain alcohol.

(5)A person with insensitive feet must always wear suitable footwear throughout the day- in the house as well as outdoors and should not walk barefoot.

·       A sandal with a strong stiff sole is ideal. If shoes are worn they should be strong, well-fitted, comfortable, and broad at the toes and the toe box (end of the shoe) should be roomy enough to accommodate the toes and as with sandals, should be worn throughout the day. The sole should be of stiff leather, and laces should be avoided.

·       Patients should always wear socks with shoes and inspect them daily. White cotton socks are preferred because they are most absorbent and because white easily shows evidence of stain or drainage.

·       Patients should inspect their shoes before and after wear to ensure that no objects have accidentally fallen into the shoe and that no sharp items have penetrated the soles. Patients should not wear high-heeled shoes, as they tend to put pressure on the forefoot.

·       Patients should inspect their feet daily for redness, warmth, swelling or any other new injury.

·       If the patient has deformed foot such as claw toes, shoes must be made especially to ensure protection of pressure points and even weight distribution. Slipper and rubber soled shoes such as tennis shoes should never be worn.

(6)Once an ulcer has formed it can be healed by bed rest (crutches are useful to ensure   100% avoidance of weight bearing). Unlike ulcers of diabetic or ischemic feet, ulcers in leprosy heal if they are protected from weight bearing. No weight-bearing is permitted until the ulcer has healed or alternatively a below-knee walking plaster is applied for about 5 weeks. To prevent the insensitive leg becoming abraded by the plaster, the foot and leg should be covered with a crepe bandage before applying the plaster of Paris. Once the plaster has been removed it is essential to supply suitable footwear to prevent the recurrence of plantar ulceration.

 

Physiotherapy is important to keep fingers mobile and to prevent contractures and teaching the patient to carry out simple exercises daily; these include fully extending paralyzed fingers by pressing the dorsal surfaces of the proximal phalanges against the thigh and massaging them while in this position or patient can wear a well-placed splint at night.

 

Educating the patient's family, friends, and employers helps in acceptance of the patient in family and in society.

 

 

Management of leprous rhinitis

 

Due to sensory loss in the nose, there is risk of trauma to the nasal septum, if the patient attempts to remove crusts by ‘picking’ his nose, resulting in ulceration. Removal of crusts by means of nasal dressing forceps is best done at the leprosy clinic, and adherent crusts can be softened by irrigation with normal saline solution. After removal of crusts, the nasal cavities are liberally smeared with a Vaseline ointment, applied on cotton-wool tipped sticks.

 

Care of the eye

 

Eyes should be regularly examined, particularly for the presence of ‘insidious iritis’ in lepromatous leprosy as it is asymptomatic, and the only means of detecting this condition is by means of the corneal microscope (slit lamp). Patients with early lagophthalmos must be encouraged to exercise the eyelids by frequent forced closure, and a tear substitute such as 5% methyl cellulose is required in order to prevent drying of the conjunctiva. The wearing of an eye shield, especially when lagophthalmos is associated with corneal anesthesia, is of proven value. When the lower lid is completely paralyzed and there is danger of exposure keratitis, lateral tarsorrhaphy, a simple operation, need to be performed to unite the eyelids at their lateral aspect.

 

Orthopedic and plastic surgery

 

Surgery has an important part to play in the rehabilitation of the leprosy patient. Surgery is required for correction of clawed fingers or toes or dropped foot. Plastic surgery is required for gynaecomastia and facial disfigurement due to excessive folds of skin. When chronic planter ulceration has not responded to conservative methods, the removal of damaged or infected metatarsal, combined with excision of the ulcer, may provide a permanent cure.

  

Other treatments

 

Dry Skin

 

This is commonly experienced in long-standing LL and usually affects arms and legs bilaterally. Mild dry skin respond to daily soaking in warm water, followed by application of white petroleum jelly to the affected skin. Severe degrees of dryness (ichthyosis), commonly associated with clofazimine treatment, respond 10% urea cream, applied to damp skin. When eczema complicates dry skin, as it often does in leprosy, a cream containing 10% urea with 1% hydrocortisone is used.

 

Breast pain and Impotence

 

Breast pain in males is due to gynaecomastia. Treatment of both the conditions is by intramuscular injections or oral administration of testosterone.

 

Prevention of disability

 

The best way to prevent disabilities is:

 

EARLY DIAGNOSIS AND PROMPT TREATMENT WITH MDT

 

The next step:

·       To recognize signs and symptoms of nerve damage due to leprosy reactions

·       To start treatment with prednisolone as quickly as possible

 

WHO Disability grading system (1988) due to leprosy:

 

Hands and feet

 

Grade 0: no anesthesia, no visible deformity or damage.

Grade1: anesthesia present, but no visible deformity or damage.

Grade2: visible deformity or damage present.

 

Damage includes ulceration, shortening, stiffness, loss of part or all of the hand or foot.

 

Eyes

 

Grade 0: No eye problem due to leprosy; no evidence of visual loss

Grade 0: eye problem due to leprosy present, but vision is not severely affected

Grade 0: severe visual impairment

Eye problems include corneal anesthesia, lagophthalmos and iridocyclitis.

 

 

Prevention of leprosy

 

The basic factors in the prevention of leprosy in endemic regions are:

1.   Case finding and prompt treatment of all leprosy cases with appropriate MDT,

2.   Keeping patient families under surveillance,

3.   Giving BCG vaccination to all new-borne infants into leprous families and to lepromin negative contacts of index cases,

4.   Improvement of socio-economic conditions, especially housing, so that members of families do not have to live in close contact and

5.   Health education and publicity about leprosy, with emphasis on early presentation for diagnosis and the likelihood of cure by MDT.

 

 

There was a WHO‐led campaign to eliminate leprosy as a public health problem. Although this focused resources and energy on leprosy, the effect of a target‐driven approach was eventually counterproductive. Leprosy patients continue to present in many countries and will need diagnosis and treatment. Leprosy is unlikely to be eradicated until there is considerable improvement in general health, wealth, living conditions and education.

 

 

 

NEWER DRUGS FOR LEPROSY TREATMENT

 

In the last two decades, new drugs with good efficacy against M. leprae have been identified and are used as alternate regimens for MB leprosy. One of the very promising newer drugs has been moxifloxacin, a broad-spectrum fluoroquinolone which is found to be the most active and more bactericidal than ofloxacin against M. leprae. The bactericidal activity of moxifloxacin is identical to that of a single dose of rifampicin. Rifapentin, a rifamycin derivative, is another drug which has pharmacokinetic properties far more favorable than rifampicin, with significantly higher peak serum concentrations and a much longer serum half-life and is observed to be more effective than a single dose of rifampicin or the combination of ROM in killing M. leprae.

 

Newer drug regimens suggested for leprosy in 2009 by the "WHO Report of the Global Programme Managers' Meeting on Leprosy Control Strategy" is as follows:  For rifampicin susceptible MB patients a fully supervised monthly regimen could include: Rifapentin 900 mg (or rifampicin 600 mg), moxifloxacin 400 mg, and clarithromycin 1000 mg (or minocycline 200 mg) for 12 months. For rifampicin-resistant patients, the intensive phase that include moxifloxacin 400 mg, clofazimine 50 mg, clarithromycin 500 mg, and minocycline 100 mg daily supervised for six months. The continuation phase comprise of moxifloxacin 400 mg, clarithromycin 1000 mg, and minocycline 200 mg once monthly, supervised for an additional 18 months.

 

 

The most important messages about leprosy for the community are:

 

1. Leprosy is like any other disease. It is caused by bacteria and is fully curable.

2. Leprosy can be easily diagnosed from clinical signs alone. A pale or reddish skin patch that lacks sensation is a tell-tale sign of the disease.

3. MDT kills the bacteria and stops the spread of leprosy after the first dose. Patients on    treatment do not spread leprosy.

4. MDT is available free of charge at all health facilities. 

5.   Early and regular treatment prevents deformities.

6.   Patients who complete treatment are totally cured, even if they have residual skin patches or disabilities.

7.   Patients can lead completely normal lives, before, during and after their treatment.