Dermatology

Leprosy (Hansen's disease, Elephantiasis)

Are You Confident of the Diagnosis?

Leprosy is a chronic granulomatous infectious disease caused by Mycobacterium leprae, which primarily affects the nerves and skin. In the generalized forms, patients may exhibit involvement of the nasal mucosa (anterior nasal septum), oral cavity (soft and hard palates), pharynx and larynx, ocular structures (sclera, episclera, ciliary body and iris), lymph nodes, viscera (eg, liver, spleen, testes, bone marrow, adrenal glands, and kidney), joints and bones (endosteum and periosteum).

According to the World Health Organization (WHO) 244,796 new cases were detected in 2009. The WHO strategies for leprosy control are based on three pillars: early diagnosis, effective free treatment and high quality patient care to prevent disabilities and provide rehabilitation.

What you should be alert for in the history

The presence of one or more cutaneous lesion(s) with loss of sensibility, sweating and/or alopecia, associated or not with thickened nerves are the hallmark features of leprosy. Major risk factors include history of traveling or inhabiting endemic areas and presence of household contacts diagnosed with leprosy.

The clinical features of leprosy are highly variable depending on the immunologic status of each individual and the duration of the disease. For instance, cutaneous lesions are absent in pure neural forms; chronic sequelae such as neuropathic plantar ulcers and/or deformities of the hands and feet may be the presenting complaints in long-standing cases. Therefore, it is important that physicians practicing in endemic countries or seeing patients from these areas, regardless of the specialty, become familiar with the multisystemic nature of the disease and the myriad presentations for early diagnosis and treatment.

Characteristic findings on physical examination

For unknown reasons, the majority of subjects that come in contact with M leprae do not contract the disease. In susceptible individuals (<5% of the population), leprosy is a disease that presents in a wide range of clinical findings (Table I), which are directly correlated with the quality of the immune response against the pathogen. Individuals who are capable of producing effective cellular responses can either achieve cure or remain in a state of controlled bacillary growth. Individuals on the other end of the spectrum who produce mainly humoral immune responses are unable to contain bacillary reproduction.

Table I.

Clinical characteristics of leprosy
I TL BT BB BL LL
Lesions Macules, often hypopigmented, not always well defined Infiltrated plaques, often hypopigmented, well defined borders Infiltrated plaques, well defined borders Plaques, central clearing, less well-defined borders Macules, papules, infiltrated plaques, less well-defined borders Macules, papules, nodules, diffuse infiltration, poorly defined margins Leonine facies: elongated soft ear lobes, saddle nose, madarosis
Sensation Decrease Absent Absent Decrease Decrease Not affected
Distribution Variable Asymmetric Asymmetric Asymmetric Tendency to symmetry Symmetric
Number 1-few 1-5 >5 >5 >5 >5
Bacilli Usually none None None-few Many Many Many (globi)
Peripheral nerves Not affected Palpable cutaneous nerve, occasional abscesses Asymmetric involvement, no more than 2 Symmetric involvement of multiple peripheral nerves Symmetric involvement of median and ulnar nerves Extensive involvement, stocking-glove sensory neuropathy

The average incubation period is 2 to 3 years (range: 6 months to 40 years or longer). The initial presentation of the disease is called the indeterminate form, as the course of the disease is unclear at that point.

INDETERMINATE FORM

In 90% of patients, the first sign of the disease is decreased sensation. First temperature sensation is lost, followed by light touch, pain and then deep pressure. The presence of anesthetic or paresthetic areas may constitute an early sign of the disease, even in the absence of cutaneous lesions.

Skin: The indeterminate form may be subclinical, or manifest as one or few hypopigmented or faintly erythematous patches (Figure 1). The cutaneous lesion is a manifestation of the peripheral nerve infection by the bacilli. The sensation is impaired in these lesions, and bacilli are usually absent.

Figure 1.

Indeterminate leprosy: Lesion of a hypopigmented macule on the forehead.

From this point onwards, the disease may resolve without sequelae or progress to one of the three forms depending on the host immunity response: tuberculoid, borderline or lepromatous as defined by the Ridley and Jopling classification in 1966.

Tuberculoid and lepromatous: polar forms are clinically stable, but the patients situated in the intermediate states may upgrade to a position of higher resistance (tuberculoid), with considerable inflammatory response, or silently downgrade to a lower resistance state (borderline and lepromatous). For instance, a borderline patient may upgrade to acquire tuberculoid characteristics (borderline tuberculoid) or downgrade to lepromatous characteristics (borderline lepromatous).

TUBERCULOID LEPROSY (TL)

This is the most resistant form of the disease; characteristically patients have effective cellular mediated immune response and the bacilli are absent in the lesions. The infection remains localized either to one skin patch or one nerve trunk, especially in the early stages (Figure 2, Figure 3).

Figure 2.

Leprosy tuberculoid form: erythematous infiltrated plaque with well-defined sharp borders.

Figure 3.

Thickened right auricular nerve and right transverse cervical nerve.

Skin: The number of cutaneous lesions may range from one to few (five). Hypopigmented or erythematous infiltrative plaques with well-defined sharp borders are observed usually in an asymmetric distribution, most commonly on the face, lateral aspect of extremities and the buttocks. The lesion may display an annular configuration, due to central clearing and peripheral expansion. The sensation is absent in the lesions, and there may be associated alopecia.

Nerves: The cutaneous nerve supply to the lesion is usually palpable, tender and enlarged. In addition, the related main peripheral nerve trunks may also be tender, thickened, and occasionally there are abscesses with calcification. Excessive edema and inflammation within the endoneurium leads to increased intraneural pressure, which if not promptly surgically corrected can lead to destruction of the Schwann cells and permanent neural damage.

Neural involvement in the absence of cutaneous lesions may be the only manifestation of the highly resistant form of the disease, especially in individuals with high cellular immunity: pure neural leprosy.

BORDERLINE (DIMORPHIC) LEPROSY:

This is an intermediate state between the two poles of the disease. The immunologic response contains bacillary growth but is unable to completely eradicate the bacilli (Figure 4, Figure 5, Figure 6).

Figure 4.

Leprosy borderline form: asymmetric dome-shaped and punched-out plaques: characteristic central clearing and less well-defined borders.

Figure 5.

Leprosy borderline form: asymmetric dome-shaped and punched-out plaques: characteristic central clearing and less well-defined borders.

Figure 6.

Leprosy borderline form: asymmetric dome-shaped and punched-out plaques: characteristic central clearing and less well-defined borders.

Borderline Borderline (BB)

This is a very unstable form of the disease, and patients may upgrade or downgrade to the characteristic polar forms.

Skin: characteristic central clearing, less well-defined borders. There are many asymmetric dome-shaped and punched-out plaques. The sensation is decreased in the lesions, and numerous bacilli are detected in the lesions.

Nerves: symmetric involvement of multiple peripheral nerves is frequent, reflecting a poor host immunologic response.

Borderline Tuberculoid (BT)

This form reflects an immunologic upgrade on the host response and is characterized by localized lesions.

Skin: infiltrated plaques, usually single with satellite lesions, or more than 5 lesions. The lesions are asymmetric and with sharp borders, and the sensation is absent. The erythema and induration are less pronounced when compared with the tuberculoid forms, but lesions may be larger (>10cm in diameter). None to few bacilli may be present in the lesions.

Nerves: asymmetric involvement, no more than two nerve trunks affected.

Borderline Lepromatous (BL)

Skin: characterized by the presence of numerous macules, papules, plaques and infiltration, with a tendency to be symmetric. The borders are less well defined; there is a classic “Swiss-cheese” appearance, with sharply marginated areas of normal skin within the plaque. The sensation is diminished. Large numbers of bacilli are present in the lesions.

Nerves: symmetric involvement of median and ulnar nerves is characteristic. Patients may have motor and sensory deficits in all four extremities.

LEPROMATOUS LEPROSY (LL)

This is a pole of high susceptibility to the bacilli. It is characterized by prevalence of humoral immune response, lack of cellular-mediated immunity, which allows abundant bacilli replication. It manifests as widespread lesions with symmetrical distribution (Figure 7, Figure 8).

Figure 7.

Leprosy lepromatous form: wide variety of lesions (macules, papules, nodules), tendency of symmetric distribution.

Figure 8.

Lepromatous leprosy

Skin: a wide variety of lesions (macules, papules, nodules) are present, with the tendency of symmetric distribution; presence of diffuse infiltration, most notable on the face (leonine facies: elongated soft ear lobes, destruction of nasal cartilage and bone). Hair loss of the eyebrows (madarosis) is common, it may progress from lateral to medial, or it can be patchy. The hair loss may extend to the eye lashes and the extremities. The sensation is not affected in the lesions and many bacilli are present, sometimes forming groups (globi).

Nerves: More extensive nerve involvement than in the tuberculoid forms. Stocking-glove sensory neuropathy is often present, with associated hand and feet trophic changes.

Subtypes

Diffuse lepromatosis: diffuse dermal infiltration and thickened dermis. More frequent in patients from the Western Mexico and Caribbean islands.

Histoid leprosy: Characterized by the presence of 3 to 50 cutaneous firm nodules, reddish or skin-colored, dome-shaped or oval papules, with regular contours deeply fixed. The lesions are distributed on the trunk, buttocks, face, extremities and overlying bony prominences, especially the elbows and knee. The surrounding skin is normal. Subcutaneous nodules and plaques may also be present. The histoid form is more common in patients with inadequate or irregular dapsone therapy.

Table I. Clinical characteristics of leprosy

Expected results of diagnostic studies

DIAGNOSTIC STUDIES FOR M leprae

HISTOPATHOLOGY

Each form of leprosy has a different histopathologic manifestation. AFB (acid fast bacilli) are visualized in bright red color in Gram, Fite, Ziehl-Neelsen or Wade stains. Methenamine silver stain is useful to detect fragment bacilli, while Sudan III stains in orange the lipid material inside the Virchow cells.

Indeterminate leprosy: Histiocytic or lymphocytic infiltrate, with reaction around or within a dermal nerve, in the subepidermal zone, around arrector pilaris muscles or around a blood vessel. AFB are absent or scanty (Figure 9).

Figure 9.

Indeterminate leprosy (H&E stain 20x): presence of a histiocytic and lymphocytic infiltrate around hair follicles, blood vessels and nerves.

Tuberculoid leprosy: Dermal granulomatous infiltrate composed of epithelioid and Langerhans giant cells, which are surrounded by lymphocytes (Figure 10). The infiltrate involves the papillary dermis up to the epidermis and follows a linear pattern along the nerves. AFB are absent or scanty.

Figure 10.

Tuberculoid leprosy (H&E stain 10x): dermal granulomatous infiltrate composed of epithelioid and Langerhans giant cells surrounded by lymphocytes.

Borderline leprosy: The findings are a mixture of the two polar forms (TL and LL). In the BT form, there are an increased number of lymphocytes and circumscription of the granulomatous response. Plasma cells are also observed, in addition to the histiocytes and lymphocytes. AFB are present.

Lepromatous leprosy: diffuse dermal infiltrate composed of macrophages abundant in bacilli and lipid droplets in the cytoplasm (Figure 11).

Figure 11.

Lepromatous leprosy (Fite-Faraco stain, oil-immersion): large number of M leprae within the vacuoles of macrophages (Virchow cells) in the lepromatous infiltrate in the dermis.

These macrophages have a foamy appearance and are called Virchow cells or lepra cells. Characteristically, there is an area of normal dermis between the infiltrate and the epidermis, which is termed the grenz zone. Lamination of the perineurium (“onion-skin” appearance) is observed on the cutaneous nerves. AFB are present in the dermis, isolated or in globi. Once the patient is under therapy, the bacilli fragment and become granular.

Histoid leprosy: well-circumscribed lesion composed of thin, spindle-shaped histiocytes forming interlacing bands and whorls. A subepidermal grenz zone is present in most cases. There are numerous bacilli and histiocytes, which may exhibit vacuolization. The bacilli are arranged longitudinally on the spindle shaped histiocytes and are termed histoid habitus.

BACILLOSCOPY

Samples can be obtained from the lesions on locations such as the earlobes, elbows, knee or the trunk. The skin must be folded and firmly squeezed using the index finger and the thumb or the forceps. A small incision is made with a scalpel blade and the lymph will be apparent. At that point, the blind side of the blade can be used to collect the lymph and smear it onto a slide. Allow it to dry and proceed with Fite or Ziehl-Neelsen stain. Microorganisms are visualized at 100x magnification with oil immersion. In 100% of LL patients, bacilli are present, while the positivity decreases to 75% in BL and 5% in TT.

The Bacillary Index (BI) is a direct measure of the bacillary load in a specific tissue. It is calculated by summing the total amount in each smear divided by 6.

BI 0 = absence of bacilli in 100 oil immersion field (OIF)

1+ = 1 to 10 bacilli in 100 OIF*

2+ = 1 to 10 bacilli in 10 OIF*

3+ = 1 to 10 bacilli in each OIF*

4+ = 10 to100 bacilli in each OIF**

5+ = 100 to 1000 bacilli in each OIF**

6+ = more than 1000 bacilli in each OIF**

*For BI 1+, 2+, and 3+: 100 OIF must be analyzed

**For BI 4+, 5+, and 6+: 25 OIF must be analyzed

It is also important to observe if the bacilli wall is intact (viable bacilli) or if the bacilli are fragmented (nonviable), and if there is globi formation.

POLYMERASE CHAIN REACTION

M leprae can be detected by PCR in fresh skin samples and split skin. The sensitivity ranges from 57% to 80% depending on the technique used.

LEPROMIN AND MITSUDA TEST

This is non-FDA approved test to detect cell-mediated immunity against M Leprae and is used mostly in Brazil. It consists of an intradermal injection of 0.1ml of a suspension containing heat-killed M Leprae. The reading is performed after 3 to 4 weeks and positive reactions manifest as a papule or nodule equal or higher than 3mm in size. The test has prognostic value (especially important for indeterminate cases), but it is not diagnostic of leprosy, since many individuals are naturally immune to the disease, without any current or prior infection. The Mitsuda reaction is negative in LL cases and positive in TT and BT patients.

In patients with erythema nodosum, a positive Mitsuda test excludes leprosy as the etiologic factor, since these reactions occur exclusively in LL patients.

ANTI-{PGL -1)TEST

ELISA (enzyme-linked immunosorbent assay) method of detecting species-specific antibody to the M leprae phenolic glycolipid-I. It is a suitable method for the detection of leprosy activity and a rapid, sensitive and inexpensive tool for the evaluation of treatment efficacy.

PILOCARPINE AND HISTAMINE TESTS

The pilocarpine test verifies the integrity of the parasympathetic nervous system by stimulating the secretion of sweat. Iodine tincture is applied in a specific lesion (and normal skin as control), followed by the injection of pilocarpine. The areas are dusted with starch powder, which turns blue if there is sudoresis. In leprosy, sweat production is diminished or absent.

In the histamine test, the sympathetic nervous system is tested by placing a drop of 0.001% histamine on the lesion and on normal skin. Both areas are pricked with a needle and after 10 minutes, a positive response manifests as erythema and the formation of a wheal. This test is especially valuable for hypopigmented leprosy lesions, in which there is no response to histamine.

ELECTRONEUROMYOGRAPHY AND NERVE BIOPSY

A study reviewing electroneuromyography (ENMG) results in 19 leprosy patients demonstrated that the axonal pattern is the most common abnormality (94.7%) followed by a demyelinating pattern in rare cases (0.5%). Mononeuropathy multiplex was the most frequent presentation (78.9%), followed by mononeuropathy simplex (10.5%) and polyneuropathy (10.5%). The nerve biopsy showed the presence of inflammatory infiltrate composed of epithelioid granuloma (42.1%), mononuclear infiltrate (36.8%) or macrophages positive for bacilli (21%), with fibrosis. Semithin sections also revealed myelinated fiber loss (94.7%), remyelination (42%), axonal degeneration (10%) as well as regeneration (31.5%).

Diagnosis confirmation

DIFFERENTIAL DIAGNOSIS FOR THE CUTANEOUS LESIONS

Hypopigmented lesions: Pityriasis alba, pityriasis versicolor, hypochromic mycosis fungoides, vitiligo, post-inflammatory hypopigmentation, hypopigmented sarcoid.

Circinate erythematous plaques: mycosis fungoides, tinea corporis, psoriasis, secondary syphilis, subacute cutaneous lupus erythematosus, lichen planus, erythema annulare centrifugum.

Granulomatous lesions, infiltrate plaques or nodules: sarcoidosis, secondary syphilis, cutaneous tuberculosis, mycosis fungoides/cutaneous lymphomas, leishmaniasis, deep fungal infections.

DIFFERENTIAL DIAGNOSIS FOR THE NEUROLOGIC LESIONS

Peripheral neuropathies: diabetes mellitus, post-herpetic neuralgia, acquired immunodeficiency syndrome (AIDS) whether from the disease or its treatment, syphilis, kidney failure, nutritional deficiencies (vitamin B12 or folate), syringomyelia, vasculitis, poliomyelitis, autoimmune diseases, lupus, rheumatoid arthritis, Guillain-Barré syndrome, exposure to toxins (heavy metals, gold compounds, lead, arsenic, mercury, and organophosphate pesticides), medications (vincristine, metronidazole, isoniazid, thalidomide), inherited disorders (amyloid polyneuropathy or Charcot-Marie-Tooth disease).

Thickened nerves: neurofibroma, diabetes mellitus, amyloidosis, Charcot-Marie-Tooth syndrome, sarcoidosis, Refsum’s disease, Roussy Levy syndrome (autosomal dominant disease, characterized by early onset of incoordination, sensory ataxia, areflexia and muscular atrophy of lower legs), Dejerine-Sottas syndrome (severe, infantile-onset demyelinating polyneuropathy syndrome), idiopathic hypertrophic neuropathy.

Acral deformities: Dupuytren’s contracture, scleroderma, tabes dorsalis.

Who is at Risk for Developing this Disease?

EPIDEMIOLOGY

Leprosy is most common in warm, wet areas in the tropics and subtropics. Worldwide prevalence is reported to be around 5.5 million, with 80% of these cases located in Brazil, India, Indonesia, Myanmar, and Nigeria.

RISK FACTORS

Location

-Residents or visitors coming from endemic areas (South America, South East Asia, Africa, Eastern Mediterranean, Western Pacific)

-Close prolonged contact with an untreated multibacillary patient

Socio-economic

-Low level of education

-Poverty

-Poor living conditions (crowding, house with sand or mud floor, low frequency of changing bed linens, bathing in open water)

-Hunting or fishing 10 years previously

Genetic

-HLA DQ1 has been related to development of multibacillary leprosy, while HLA-DR2 and DR3 have been correlated with paucibacillary leprosy

-Polymorphisms in genes that encode: tumor necrosis factor (TNF) –α, interleukin (IL)-10, vitamin D receptor, and toll-like receptor (TLR) 2-6q25-q26 has been termed the leprosy susceptibility locus, and studies in Vietnam and Brazil correlated the presence of this allele with increase in risk of having leprosy.

-PARK2/PACRG gene: further investigation of the chromosome regions 6q25–q26, 6p21, 10p13 and 20p12–p13, identified four of the six SNPs associated with leprosy (P < .05) localized to the putative PARK2 promoter overlapping the 5’-regulatory region of the adjacent PACRG gene. The odds ratio of leprosy for individuals carrying at least one haplotype with both risk alleles (PARK2_e01(-2599) –T and rs1040079-C) was 5.28 (95% CI [2.06–13.55]).

-NRAMP1 (natural resistance-associated macrophage protein1): chromosome region 2q35. It has been correlated with different forms of the disease, probably due to its influence in the expression of major histocompatibility complex class II, TNF-α and nitric oxide synthase induction.

The PARK2/PACRG and NRAMP1 genes expression has been closely correlated with the innate immune response, and monocyte, macrophage and dendritic cells activity.

What is the Cause of the Disease?

Etiology

Leprosy is caused by M leprae, an obligate intracellular, gram-positive, acid-fast, rod-shaped bacterium. It measures 1 to 8µm in diameter and reproduces under favorable temperatures (27º to 30ºC /81º to 86ºF) by binary fission every 12 to 13 days, reaching plateau growth phase in 20 to 40 days. M leprae cannot be cultured, but it remains viable in the environment under certain specific thermal-hydrologic regimes: hot and humid weather, wet soils and in the presence of water. Humans are the major reservoirs of M leprae while wild nine-banded armadillos are the only environmental carriers that may develop multibacillary disease.

Most recently a new bacilli M lepromatosis has been identified in four fatal cases of diffuse lepromatous leprosy or diffuse leprosy of Lucio and Latapi. The genome differs from the M leprae genome in 2.1% of the 16S rRNA gene and in 6% to 14% mismatches among five less conserved genes. No consensus has been reached yet on how to classify it as new species or a separate strain of M leprae.

The exact mode of the disease transmission is still unknown. The most accepted hypothesis is that the bacilli gain access to the circulation by nasal inhalation of contaminated secretions, followed by invasion of macrophages and Schwann cells. Alternative proposed modes of transmission are direct contact with the cutaneous lesion; use of infected tattoo needles; contact with infected soil or sphagnum moss; exposure to insect, arthropod vectors or congenital transmission.

Pathophysiology

The majority of individuals are naturally resistant to M leprae infection. In susceptible individuals, M leprae infects macrophages and Schwann cells, with subsequent neural damage and cutaneous manifestations. The extent and severity of the disease is directly correlated to the capacity of each individual to form an effective cell-mediated immune response against the mycobacteria. Both the innate and the adaptive immune systems are involved in the host defense against M leprae.

THE INNATE IMMUNE SYSTEM

The first host response to the invading M leprae is mediated by the innate immune system. Cells of the innate immune system express germline-encoded pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). Following the binding of a specific PRP with its receptor, phagocytosis of the pathogen occurs. A cascade of inflammatory events is triggered to promote phagosome lysosomal fusion and induction of cell-mediated immune response.

Toll-like receptors (TLRs) 1 and 2 are a class of PRPs that recognize specific M leprae PAMPs. The activation of the TLR2/1 heterodimer by M leprae lipopeptides triggers the production of TNF-α and IL-12, which promote Th1 cytokine response. TLR1 and TLR2 are strongly expressed on macrophages in lesions from the localized TT as compared with LL. In addition, Th1 cytokines (INF-γ, GM-CSF, IL-12, and IL-18) enhance TLR 2/1 activation, whereas Th2 cytokines (IL-4 and IL-10) inhibit the activation. Th1 cytokines also upregulate TLR 2/1 responses, and TLR1 expression in monocytes. Thus, the local cytokine milieu directly affects TLRs activation and expression, and as a consequence, the differentiation to Th1 or Th2 response. Polymorphisms in the TLR1 gene have been implicated with decreased TLR2/1 responses and the pathogenesis of leprosy.

THE ADAPTIVE IMMUNE SYSTEM

Dendritic cells (DC) are antigen-presenting cells highly efficient in activation of T cell responses, which constitute the cell-cmediated immunity against the pathogen. DCs process antigens and present them to CD8+ T cells via class I MHC (major histocompatibility complex) molecules or to CD4+ T cells via class II MHC. In addition to the polymorphic MHC molecules, the CD1 family of non-polymorphic antigen-presenting molecules has been identified in the antigen presentation process in leprosy. LL lesions are characterized by a deficit in CD1b+ DC, indicating that this pathway plays an important role in host defense against mycobacterial infection.

The indeterminate form is the first manifestation of the disease and depending upon the level of each organism immune response, the disease will follow one of three courses:

-Adequate cellular immune response: The disease will completely resolve without sequelae, and cure will be achieved.

-Limited cellular immune response: The Th1 CD4+-cell-mediated immune response mediated by IL-2, TNF-β and interferon (INF)-γ leads to the formation of delineated granulomas that effectively control bacterial replication. This response maintains an inflammatory state; however, it is not effective enough to completely eliminate the bacilli. As a result, there are few bacilli in the lesions and limited clinical expression of the disease, ie, fewer cutaneous lesions and restricted neural damage. These forms are called paucibacillary by the WHO classification (see treatment section) and with limited accuracy correspond to TT and BT in the Ridley-Jopling classification.

-Deficient cellular immune response, predominance of humoral immune response: T helper (Th) 2 response leads to the release of IL-4, IL-5, IL-10 and IL-13, which suppresses macrophage activity and granuloma formation. This allows uncontrolled bacterial replication and continuous infiltration of the skin and nerves. Multibacillary forms (BB, BL, LL) present with disseminated lesions, multiple nerve compromise and presence of numerous bacilli.

The neurotropism is due to the interactions between two molecules on the M leprae cell wall: phenolic glycolipid-1 (PGL-1) and M leprae laminin-binding protein (LBP21)] with the α2 side chain of laminin-2 located in the basal lamina of Schwann cells. The binding allows the entry of the microorganism in the Schwann cell, which in turn deactivates myelin gene transcription and promotes myelin-free cell growth, triggering an inflammatory process. The consequence is granuloma formation and nerve destruction.

Systemic Implications and Complications

NEUROLOGIC MANIFESTATIONS

Neural compromise is present on all forms of leprosy. It may manifest as:

Thickened nerves: Palpation of nerves is mandatory in all leprosy patients. The following nerves may be affected:

-Head: facial nerves branches (temporal, zygomatic, buccal, marginal mandibular), cervical and greater auricular nerves.

-Upper extremities: ulnar, radial, median nerves and the cutaneous branch of the radial nerve.

-Lower extremities: common peroneal and posterior tibial nerves.

Acute neuritis: shooting pain over an extremity and painful thickened nerves on palpation

Chronic neuropathic changes: sensory loss, muscle weakness or atrophy, flexion contractures of the fourth and fifth finger, secretory disturbances (dry eyes, nose), vasomotor alterations, acquired ichthyosis

Sympathetic nerve involvement: palmo-plantar anhidrosis

Sequelae: deformities of the hands and feet (ulnar claw, “hammer” toes), and neurotrophic plantar ulcers.

OCULAR MANIFESTATIONS

Loss of sensation in the cornea is common in all forms of leprosy. Lagophthalmos, corneal sensory loss, episcleritis, keratitis, and blindness may be a consequence of leprosy. Iritis may occur de novo or in association with reactions.

RESPIRATORY MANIFESTATIONS

Complications are common in LL cases and include septal perforation, nasal collapse (saddle nose), rhinitis, and hoarseness due to vocal cord nodules.

Genito-urinary manifestations: Orchitis leading to gynecomastia, impotence and sterility is a major problem and often overlooked.

Kidney damage may be a consequence of treatment or the disease itself. Renal function abnormalities are common in leprosy, especially in long-standing untreated lepromatous leprosy cases. In a review of 199 autopsies of leprosy patients, 144 patients had the following renal lesions: amyloidosis (31%), glomerulonephritis (14%), nephrosclerosis (11%), tubulointerstitial nephritis (9%), granuloma (1%), and other lesions (6%). Most patients with amyloidosis presented with proteinuria (95%) and renal failure (88%).

Rheumatologic manifestations: Carpal-tunnel syndrome, acute symmetric polyarthritis or swollen hands and feet (during type 2 reactions), Charcot's arthropathy, insidious-onset chronic symmetric polyarthritis similar to rheumatoid arthritis, isolated tenosynovitis or tenosynovitis associated with arthritis or neuropathy. Articular involvement may be the sole presenting manifestation even without cutaneous lesions. Other rheumatologic manifestations occasionally reported are enthesitis, sacroiliitis, cryoglobulinemic vasculitis.

Patients diagnosed with leprosy may have auto-antibodies such as rheumatoid factor, LE (lupus erythematosus) cell, anti-nuclear antibodies, and anticardiolipin Ig-M. However, anti-CCP antibodies are negative in leprosy and thus may serve as a useful serologic marker to differentiate it from rheumatoid arthritis. Thrombotic events have been reported in patients with leprosy, especially undergoing type 2 reactions, and/or with concomitant thalidomide and corticosteroid use.

Treatment Options

In 1997 the WHO created an operational classification for leprosy to facilitate treatment guidelines in areas where few diagnostic tools are available (Table I). The classification is solely based on the number of lesions:

Paucibacillary (PB single lesion) leprosy

Paucibacillary (PB) leprosy: 2 to 5 lesions OR only one nerve involvement

Multibacillary (MB) leprosy: more than 5 lesions OR more than one nerve involvement

WHO treatment guidelines for leprosy are summarized in Table II.

Table II.

WHO treatment guidelines for leprosy
Rifampicin(Rifampin) Clofazimine Dapsone Ofloxacin Minocycline Duration
Adults
Multibacillary 600mg once a month 50mg daily300mg once a month 100mg daily 12 months
Paucibacillary 600mg once a month 100mg daily 6 months
Paucibacillary(single lesion) 600mg single dose 400mg single dose 100mg single dose Single dose
Children(if <10yo adjust for body weight)
10-14yo multibacillary 450mg once a month 50mg daily150mg once a month 50mg daily 12 months
10-14yo paucibacillary 450mg once a month 50mg daily 6 months

As of 1995, WHO recommends 1 year of multidrug treatment (MDT) for MB patients (12 pulses in 18 months) and 6 months (six pulses in 9 months) for PB patients. For operational purposes, once a patient receives adequate chemotherapy, he is considered “cured.” Histopathologic resolution of the lesions and clinical subsidence of the disease may take place months to years after MDT is stopped.

MDT is generally safe and effective; with cure being achieved in almost all cases and interruption of disease transmission being observed early in the course of treatment (patients are no longer infectious to others after the first dose). Relapses and drug resistance are rare. An analysis of 213 relapse cases in six endemic countries revealed that 98% presented with new skin lesions at the time of the diagnosis of relapse and 88% had an increase in the bacteriologic index of 2 units or more. Drug resistance was observed in 12 of 203 cases for dapsone, 9 of 216 for rifampicin, 2 of 170 for ofloxacin.

The most common causes of treatment failure include

-Initial mistaken diagnosis and treatment of multibacillary cases as paucibacillary

-Noncompliance

-Drug resistance

-Relapse after apparent cure

-Persistence

Optimal Therapeutic Approach for this Disease

Pregnancy and leprosy: Since pregnancy induces a decrease in cellular immunity, it is not infrequent to see the first signs of leprosy during pregnancy or during the postpartum period. Pregnancy and lactation do not contraindicate MDT; however the newborns may show hyperpigmentation of the skin due to clofazimine, which tends to regress after MDT discontinuation.

Tuberculosis and leprosy: The rifampicin dose should be adjusted to match the dose prescribed to treat tuberculosis, which is 600mg/day, to avoid induction of M tuberculosis resistance.

AIDS and leprosy: MDT treatment should be used for all patients.

Patient Management

In the United States, five-year follow-up every 6 months is recommended for PB patients and 10-year follow-up at 6 months intervals for MB cases. All household contacts should be examined and BCG vaccination is recommended in some countries, although the efficacy is controversial.

The main side effects of MDT include:

Rifampicin

-Skin: Facial erythema, pruritus, generalized rash

-Gastrointestinal: Loss of appetite, nausea, vomiting, and abdominal pain. Elevation of liver enzymes (ALT, AST) and bilirubin may occur, treatment must be discontinued and the patient should be immediately evaluated.

-Hematologic: thrombocytopenia, purpura, abnormal bleeding, hemolytic anemia

-Others: with intermittent rifampicin dosage regimens a reaction characterized by fever, chills, headache, dizziness, and bone pain may occur (“flu-like syndrome”).

-When rifampicin and oral contraceptives are used concomitantly, there is decreased effectiveness of oral contraceptives.

Clofazimine

-Skin: ichthyosis and dryness, pigmentation from pink to brownish-black, rash and pruritus

-Gastrointestinal: abdominal and epigastric pain, diarrhea, nausea, vomiting, gastrointestinal intolerance

-Ocular: conjunctival and corneal pigmentation due to clofazimine crystal deposits; dryness; burning; itching; irritation.

-Others: discoloration of urine, feces, sputum, and sweat; elevated blood glucose levels

Dapsone

-Hematologic: hemolysis is the most common adverse effect and is seen in patients with or without G6PD deficiency

-Gastrointestinal: nausea, vomiting, abdominal pain, and pancreatitis

-Nervous System: peripheral neuropathy

-Others: vertigo, blurred vision, tinnitus, insomnia, fever, headache, psychosis, phototoxicity, pulmonary eosinophilia, tachycardia, albuminuria, the nephrotic syndrome, hypoalbuminemia without proteinuria, renal papillary necrosis, male infertility, drug-induced lupus erythematosus and an infectious mononucleosis-like syndrome.

Unusual Clinical Scenarios to Consider in Patient Management

REACTIONAL EPISODES

During the course of untreated or even treated leprosy, the immune system may produce inflammatory reactions that manifest as reactional episodes. Any form of leprosy can be affected, except for the indeterminate form, and it is more frequent in borderline patients.

Common triggers are MDT initiation, acute infections, pregnancy, mental stress, and other infections. Oral infections are common in developing countries and generally overlooked causes of reaction episodes.

Type 1 reaction (reversal reaction): There is an upgrade in the cellular immune response, which manifests as increased inflammation in the pre-existing lesion, sometimes with the appearance of new lesions in the proximity called satellite lesions (Figure 12) . There is acute nerve pain (neuritis), associated or not with loss of function. A more prolonged (<6 months) course may be present, characterized by progressive nerve function impairment in the absence of neuritis. Diffuse edema of hands and feet and leukocytosis may be present. Treatment is with oral prednisone 20 to 60mg/day).

Figure 12.

Type 1 reaction: presence of intense inflammatory process in the pre-existing lesions, most noticeable in the periorificial areas. New smaller lesions are visible in the proximity (satellite lesions).

Type 2 reaction: Vasculitis: erythema nodosum leprosum, bullous erythema nodosum, necrotizing erythema nodosum, erythema multiforme and bullous erythema multiforme. See Erythema Nodosum Leprosum chapter 976.

LUCIO LEPROSY AND LUCIO PHENOMENON

Lucio leprosy is a rare form of LL that generally affects patients in Mexico, Costa Rica, and the Gulf coast. It is characterized by diffuse infiltration of the skin and often accompanied by reactional episodes of thrombotic phenomena as well as necrotizing cutaneous small vessel vasculitis, called Lucio phenomenon. Clinically it manifests as multiple deep ulcers over the extremities and gluteal regions, eroding subcutaneous tissue with ragged margins.

Histopathologic studies demonstrate an ulcerated epidermis and dermis along with foamy macrophages, ischemic necrotizing vasculitis, fibrinoid necrosis and new vessel formation with clumps of acid-fast bacilli periadnexally, perivascularly, and within macrophages and endothelial cells.

Treatment is with oral prednisone 20 to 60mg/day).

What is the Evidence?

Nakayama, EE, Ura, S, Fleury, RN, Soares, V. "Renal lesions in leprosy: a retrospective study of 199 autopsies". Am J Kidney Dis. vol. 38. 2001. pp. 26-30.

(A postmortem review of renal lesions in patients diagnosed with leprosy.)

Chauhan, S, Wakhlu, A, Agarwal, V. "Arthritis in leprosy". Rheumatology (Oxford). vol. 49. 2010. pp. 2237-42.

(A comprehensive review of all rheumatologic manifestations in patients with leprosy)

"Surveillance of drug resistance in leprosy: 2009". Wkly Epidemiol Rec. vol. 85. 2010. pp. 281-4.

(WHO report on drug resistance for different countries)

"Global leprosy situation, 2010". Wkly Epidemiol Rec. vol. 85. 2010. pp. 337-48.

(Epidemiologic data on leprosy worldwide, according to the WHO database)

Souza, AD, el-Azhary, RA, Foss, NT. "Management of chronic diseases: an overview of the Brazilian governmental leprosy program". Int J Dermatol. vol. 48. 2009. pp. 109-16.

(Comprehensive review of the Brazilian health care system based on the leprosy management; this article also brings a review of leprosy epidemiology and treatment.)

Zenha, EM, Ferreira, MA, Foss, NT. "Use of anti-PGL-1 antibodies to monitor therapy regimes in leprosy patients". Braz J Med Biol Res. vol. 42. 2009. pp. 968-72.

(Clinical study comparing anti-PGL-1 levels with bacillary index and treatment outcomes)

Jardim, MR, Chimelli, L, Faria, SC, Fernandes, PV, Da Costa Néri, JA, Sales, AM. "Clinical, electroneuromyographic and morphological studies of pure neural leprosy in a Brazilian referral centre". Lepr Rev. vol. 75. 2004. pp. 242-53.

(Neurologic manifestations and electroneuromyography results in patients with leprosy)

Alter, A, Alcaïs, A, Abel, L, Schurr, E. "Leprosy as a genetic model for susceptibility to common infectious diseases". Hum Genet. vol. 23. 2008. pp. 227-35.

(Detailed explanation on the genetic background of leprosy patient and correlation with disease activity and subtype)

Motta, AC, Furini, RB, Simão, JC, Ferreira, MA, Komesu, MC, Foss, NT. "The recurrence of leprosy reactional episodes could be associated with oral chronic infections and expression of serum IL-1, TNF-alpha, IL-6, IFN-gamma and IL-10". Braz Dent J. vol. 21. 2010. pp. 158-64.

(Experimental study that measured serum inflammatory biomarkers and correlated them with the clinical activity of leprosy)

Blacwell, JM, Searle, S, Goswami, T, Miller, EN. "Understanding the multiple functions of Nramp1". Microbes Infect. vol. 2. 2000. pp. 317-21.

(Review on Nramp1)

Han, XY, Seo, YH, Sizer, KC, Schoberle, T, May, GS, Spencer, JS. "A new Mycobacterium species causing diffuse lepromatous leprosy". Am J Clin Pathol. vol. 130. 2008. pp. 856-64.

(Case report of a patient with diffuse lepromatous and the detection of a new Mycobacterium species)

Ang, P, Tay, YK, Ng, SK, Seow, CS. "Fatal Lucio's phenomenon in 2 patients with previously undiagnosed leprosy". J Am Acad Dermatol. vol. 48. 2003. pp. 958-61.

(Case report of two patients with diffuse leprosy and detection of a new Mycobacterium species)

Worobec, SM. "Treatment of leprosy/Hansen's disease in the early 21st century". Dermatol Ther. vol. 22. 2009. pp. 518-37.

(A review article on leprosy treatment and current WHO recommendations)
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