Chapter 186. Leprosy

Risk factors are birth or residence in a known endemic area, a family member with leprosy, reflecting common genetic susceptibility, environmental exposure, or both, and, as with many other infections, poverty. Therapeutic use of anti-tumor necrosis factor (TNF) antibodies and the immune reconstitution inflammatory syndrome (IRIS) of highly active antiretroviral therapy (HAART) have been associated with the onset of leprosy.15,16

Mycobacterium leprae, the cause of leprosy, is a noncultivable, Gram-positive, obligate intracellular, acid-fast bacillus. Sequencing of the bacillary genome17 revealed gene deletion and decay leaving M. leprae with few respiratory enzymes, providing an explanation for the failure to cultivate the organism in cell-free media, as well as for its obligatory intracellular environment. In tissues or smears, M. leprae is quantified by the biopsy index (BI), a logarithmic scale as to the numbers of bacilli per oil immersion field (OIF): a BI of 6 is 1,000 or more bacilli/OIF; a BI of 5 is 100–1,000/OIF; a BI of 4 is 10–100/OIF; a BI of 3 is 1–10/OIF; a BI of 2 is 1 bacillus/1–10 OIFs; a BI of 1 is 1 bacillus/10–100 OIFs; and a BI of 0 is no bacilli in 100 OIFs. Because a BI of 6 indicates 109 bacilli per gram of granuloma, tissue with a BI of 0, may have as many as 103 organisms per gram.

The bacillary cell wall consists of a peptidoglycan backbone linked to arabinogalactan and mycolic acids. Immunogenic proteins are associated with the cell wall, and also are present in the cytoplasm. The cell-wall-associated lipoproteins, ligands for pattern recognition receptors (PRRs) such as TLR2 and NOD2 of the innate immune system, probably initiate the host's first response M. leprae. This response may be important in determining the eventual clinical outcome.18 A lipoglycan target of both antibody and cellular immune responses, lipoarabinomannan, courses through the outer membrane and inserts into the cell membrane. Phenolic glycolipid I is a major, species specific and immunogenic constituent of the highly nonpolar outer layer of the bacillus. Entry into nerves is mediated by the binding of the species-specific trisaccharide in phenolic glycolipid I to laminin-2 in the basal lamina of Schwann cell–axon units,19 providing a rationale for why M. leprae is the only bacterium known to invade peripheral nerves.

A twin study has provided compelling evidence that both genetic and environmental factors are important in determining disease susceptibility and expression.20 A region on chromosome 10p13, including the PARK2 and PACRG, loci for susceptibility to Parkinson's disease, has been found to also contain a risk factor for the development of leprosy.21 This includes both tuberculoid and lepromatous forms, and has been identified in a number of genetically diverse populations, but not all. Major histocompatibility complex class II antigens appear to influence the clinical presentation, but not disease susceptibility,22 while PRRs such as the TLRs and NOD2 may influence both.23–27 The great majority of people exposed to M. leprae are presumed to make a curative immunologic response, while the clinical presentation of the granulomatous spectrum of leprosy provides an immunologic spectrum of host defense, thus providing an exemplary model for examining cell-mediated immunity (CMI) in humans.

History

For physicians practicing in nonendemic areas, learning that the patient has risk factors for leprosy, i.e., birth or residence in an endemic area, or a blood relative with leprosy may lead to a correct diagnosis of leprosy.

Historic data or symptoms that should elicit further suspicion of leprosy include complaints referable to peripheral neuropathy, persistent nasal stuffiness, ocular symptoms, and, in young men, loss of sexual drive or infertility.

Cutaneous Lesions

The Granulomatous Spectrum

Ridley and his associates provided the most detailed description of the granulomatous spectrum of leprosy,28,29 integrating both clinical and histologic changes. Ridley's construct is a six-member spectrum, ranging from high to low resistance, TT (polar tuberculoid), BT (borderline tuberculoid), BB (borderline), BL (borderline lepromatous), LLs (subpolar lepromatous), and, finally, LLp (polar lepromatous):

Conceptually, TT and LLp are clinically stable, but, between the poles, the host response may change, as indicated by the arrows, upgrading (or reversing) to a state of higher resistance, often with devastating inflammation, or downgrading to a posture of lower resistance, usually silent but occasionally inflammatory. BT patients may upgrade to TT, thus, becoming stable, but LLs patients do not downgrade to LLp nor do LLp patients upgrade. (“LL” includes both LLs and LLp patients.) The host's granulomatous response is the result of the degree of CMI directed against M. leprae. The classification is determined primarily by clinical and histologic changes, bacillary numbers being a secondary consideration. Patients along the clinical spectrum of leprosy are presumed to be manifestations of evolving immune responses, which, based on environmental and genetic factors, will eventually gravitate toward one of the two poles.

In comparison of pre-Ridley and Ridley terminology, “tuberculoid” corresponds to TT and BT, “borderline” or “dimorphic” to BB and BL, and “lepromatous” to LLs and LLp. In virtually all TT patients, and in most BT cases, acid-fast bacilli (AFB) cannot be found, whereas in BB, BL, LLs, and LLp, bacilli are demonstrable with ease. Ridley's construct is useful in classifying patients, especially for immunity.

Peripheral Nerve Changes

Five types of peripheral nerve abnormalities are common in leprosy. (1) Nerve enlargement (usually perceived as asymmetry), particularly in those close to the skin, generally thought to be due to the fact that those locations are coolest in temperature, such as the great auricular, ulnar, radial cutaneous, superficial peroneal, sural, and posterior tibial. (2) Sensory impairment in skin lesions. (3) Nerve trunk palsies either with signs and symptoms of inflammation or without such overt manifestations, that is, silent neuropathy,30 usually with both sensory and motor loss (weakness and/or atrophy) and, if long standing, also with contracture. (4) Stocking-glove pattern of sensory impairment (S-GPSI), with a slow loss of type C fibers, involving heat and cold discrimination before loss of pain or light touch, beginning in acral areas and, over time, extending centrally but initially sparing the palms. (5) Anhidrosis on palms or soles suggests sympathetic nerve involvement.

Polar Tuberculoid Leprosy

In TT leprosy immunity is strong as manifested by spontaneous cure and the absence of downgrading to a posture of less host resistance. The primary skin lesion of TT is a sharply marginated plaque, often annular secondary to peripheral propagation and central clearing. Typically, the lesion is firmly indurated, elevated, erythematous, scaly, dry, hairless, and hypopigmented (Fig. 186-1), but clinically, considerable variation is encountered (eFig. 186-1.1).

A nearby sensory nerve may or may not be enlarged (eFig. 186-1.1), but the lesion itself is characteristically anesthetic and anhidrotic. Skin lesions are often solitary, particularly in those patients who are TT de novo, as contrasted to those who upgrade to TT from BT, where multiple lesions, usually no more than three, may be found. In both groups, immunity is sufficient to affect cure, thus, placing an upper limit of 10 cm on lesion size, but antibiotic therapy is recommended.

TT Histology

In de novo TT lesions, small, well-developed epithelioid tubercles are surrounded by large lymphocytic mantles, but are uncommonly seen. In TT upgrading from BT, abundant Langhans-type giant cells and a brisk exocytosis into the epidermis are usually found in addition to the lymphocytic mantle (Fig. 186-2). Rarely caseation necrosis is seen, and, if present, warrants the classification of TT (eFig. 186-2.1). AFB are not found.

Borderline Tuberculoid Leprosy

In BT disease (Fig. 186-3 and eFigs. 186-3.1 and 186-3.2), immunologic resistance is strong enough to restrain the infection, in that the disease is limited and bacillary growth retarded, but the host response is insufficient to self-cure. These patients are somewhat unstable—resistance may increase, upgrading to TT, or decrease, downgrading to BL.

The primary skin lesions of BT are plaques and papules (Box 186-1). As in TT, an annular configuration is common and both borders are sharply marginated but annular lesions or plaques may have sharply marginated satellite papules (Fig. 186-3). Hypopigmentation may be conspicuous in darkly pigmented patients (eFig. 186-3.1). In contrast to TT, typically, there is little or no scaling, less erythema, less induration, and less elevation, but lesions may become much larger, that is, well over 10 cm in diameter, a single lesion sometimes involving an entire extremity over time (eFig. 186-3.1). Multiple, asymmetric lesions are the rule, but solitary lesions are not rare. Impairment of sensation in skin lesions is the rule and nerve trunk involvement, enlargement or palsies, usually in no more than two and asymmetric, are common. Nerve abscesses, when they occur, are most often seen in males with BT disease (eFig. 186-3.2).

BT Histology

In BT tissues, well-organized epithelioid tubercles are present but the lymphocytic mantles are less well developed than in TT disease (eFigs. 186-3.3 and 186-3.4). Also, Langhans-type giant cells are inconstant. Epidermal exocytosis, if present at all, is focal. AFB are only rarely seen in BT. The presence of AFB or plasma cells in what otherwise appears to be BT warrants consideration of a reversal reaction.

Borderline Leprosy

BB is the immunologic midpoint or midzone of the granulomatous spectrum, being its most unstable area, with patients quickly up- or downgrading to a more stable granulomatous posture with or without a clinical reaction. Characteristic skin changes are said to be annular lesions with sharply marginated interior and exterior margins, large plaques with islands of clinically normal skin within the plaque, giving a “Swiss cheese” appearance, or the classic dimorphic lesion. Because of instability, the BB posture is short lived and such patients are rarely seen. For example, we have yet to see a nonreactional patient meeting both clinical and histologic criteria.

BB Histology

In BB, the epithelioid differentiation remains, but lymphocytes are sparse, giant cells are absent, and bacilli are easily found.

Borderline Lepromatous Leprosy

In BL disease, resistance is too low to significantly restrain bacillary proliferation, but still sufficient to induce tissue destructive inflammation, especially in nerves. Thus, BL patients have the worst of both worlds. The BL category is highly variable in its clinical expression (eFigs. 186-3.5 and Fig. 186-4). Although seen in only a third of BL patients, the classic dimorphic lesion is the most characteristic, having an annular configuration with a poorly marginated outer border (lepromatous like) but a sharply marginated inner one (tuberculoid like), hence, having both morphologies thus “dimorphic leprosy.” Variation may be considerable in one patient and even greater across the entire BL population. Poorly or sharply marginated plaques with “punched out” or “Swiss cheese” sharply marginated areas of normal skin in the interior of the plaque are also characteristic, and can be thought of as a variant of the classic dimorphic lesion (eFig. 186-3.5). Annular lesions with sharply marginated exterior and interior borders are not uncommon. Lepromatous-like, poorly defined papules and nodules may be numerous, but are usually accompanied by sharply marginated lesions somewhere.

Lesions range in number from solitary to numerous and widespread. Generally, the annular and plaque lesions are asymmetrically distributed, but the lepromatous-like nodules, if numerous, are symmetric (Fig. 186-4). Skin lesions are often hypesthetic or anesthetic, but not necessarily so. Nerve trunk palsies have their highest prevalence in BL disease, but are variable in number, ranging from none to serious neurologic deficits, both motor and sensory, in all four extremities. Involvement of both median and ulnar nerves, not infrequently bilateral, is characteristic. When disease is extensive, BL patients may also develop S-GPSI.

Untreated BL patients have slow relentless progression of skin and nerve changes. With or without treatment, this course may be altered by a reactional state (see section below), upgrading or reversal reactions being more common than erythema nodosum leprosum (ENL). Also, BL patients may silently downgrade to an LLs granulomatous posture.

Borderline Lepromatous Histology

One classic BL dermal response is a relatively dense lymphocytic infiltrate restricted to the space occupied by the macrophages (eFig. 186-4.1). The macrophages are often foamy, but undifferentiated macrophages may be common. The epidermis is undisturbed. In nerves, the other classic BL response is lamination of the perineurium with infiltration by inflammatory cells (eFig. 186-4.2). In BL, as contrasted to LLs, the inflammatory infiltrate is so dense as to obscure the lamination. An alternative BL pattern is that of a chronic lymphohistiocytic infiltrate (eFigs. 186-4.3 and 186-4.4A). Plasma cells may be present. Bacilli are easily found, and globi are not unusual.

Lepromatous Leprosy

In lepromatous leprosy (LL) the diminished CMI toward M. leprae permits unrestricted bacillary replication and widely disseminated, multiorgan disease. Diffuse dermal infiltration is always present subclinically and, may be overtly manifested by enlargement of ear lobes, widening of the nasal root, fusiform swelling of the fingers, and the skin being thrown into folds. Poorly defined nodules are the most common lesions, usually up to 2 cm in diameter, and are symmetrically distributed. A conjunction of skin folding and nodule formation produces the “leonine faces.”

Dermatofibroma-like or histiocytoma-like lesions, usually multiple, are sharply marginated erythematous papules or nodules, sometimes confluent into plaques (Fig. 186-5A and 186-5B). These were first identified in relapsing patients as “histoid” leprosy, but are not unusual as presenting lesions. Less common presenting skin lesions include digitate, barely indurated patches of erythema (Fig. 186-6), which in light-skinned patients are sometimes followed by a mild hyperpigmentation, a veil of melanin concealing the erythema; in dark-skinned patients multiple hypopigmented macules may be seen. Also, rarely, a dense dermal infiltrate may mimic a nevoid lesion (see eFig. 186-6.1).

A clinical clue of LLs is a sharply marginated region in a lesion, perhaps the residual of a BL lesion in a patient who has downgraded to LLs, or the presence of dermatofibroma-like lesions. The distinction between LLs and LLp is usually made histopathologically.

Hair loss is most common in the eyebrows (eFig. 186-6.2), where it may progress medially to laterally or be patchy. Hair loss may also occur on the eyelashes and extremities, and may be partially reversible if treated early. Scalp involvement is rare. Loss of eccrine sweating from sympathetic nerve involvement is common, as manifested by dry palms or soles. Any given skin lesion may or may not be hypoesthetic but generally, in each patient, some are. Nerve trunk palsies occur, but are less common than in BL. The stocking glove pattern of sensory impairment is common and may be so severe as to lead to debilitating trophic changes of the hands or feet.

Untreated LL disease is relentlessly progressive, but this course may be altered by reactional states. LLs and LLp subjects frequently develop erythema nodosum leprosum (ENL). LLp patients do not develop reversal reactions (see below), whereas LLs patients may.

LL Histology

LLs and LLp have many histologic features in common. (1) Nodular lesions, consisting mainly of foamy or undifferentiated macrophages, have replaced much of the dermis, with loss of appendages. The epidermis is attenuated by the nodule, but a thin layer of dermis (grenz zone) separates the two and a Fite stain shows numerous bacilli. (2) Clinically normal skin will show a variably dense infiltrate of foamy or undifferentiated macrophages, often scant in a perivascular and periappendageal distribution, but the epidermis is undisturbed (eFig. 186-6.3). (3) Both LLs and LLp may show small but dense aggregates of lymphocytes, which may be B-cells. (4) The appearance of the macrophages varies with the age of the lesion, ranging from undifferentiated to foamy cells (eFigs. 186-6.4 and 186-6.5). (5) Endothelial AFB are not uncommon in LLs and LLp. (6) Plasma cells and mast cells, the latter often easily identified by the AFB counter stain, are sometimes increased. (7) In older lesions, foreign-body giant cells may be common, probably arising in response to the death of macrophages containing many dead AFB (eFig. 186-6.6).

In LLs, lymphocytes are sparsely distributed generally, and the perineurium is laminated, but sparsely infiltrated by inflammatory cells making the laminations conspicuous (see eFig. 186-6.7). In LLp, lymphocytes are fewer than in LLs, and the perineurium is undisturbed (see eFig. 186-6.8). In our experience, the dermatofibroma-like lesions have all been in LLs patients, may resemble dermatofibromas histologically as well as clinically (eFig. 186-6.9).

Indeterminate Leprosy

Indeterminate leprosy is a term with nearly as many meanings as it has users. We prefer the definition of Khanolkar,31 designating an early lesion appearing before the host makes a definitive immunologic commitment to a curative or overt granulomatous response. Clinically, the indeterminate lesion is a hypopigmented macule or patch, with or without an associated sensory deficit in or near the defect, and AFB, if found, are present in very small numbers. Such lesions are rare. The term is sometimes used, inappropriately in our opinion, to describe lesions rich in bacilli but having neither typical tuberculoid nor lepromatous histological patterns. Such patients are usually BL or occasionally LL.

Indeterminate Leprosy Histology

The indeterminate lesions usually show a patchy infiltrate in both the papillary and reticular dermis, consisting of lymphocytes and a few macrophages. Bacilli are rare or are not found. If bacilli are present in good numbers then BL or LL disease is much more likely than “indeterminate leprosy.”

Related Physical Findings

Insensitivity of the cornea is common in all forms of leprosy. In BL and LL diseases, numerous changes in the cornea and anterior chamber are possible. Iritis is a common serious change, occurring de novo or in association with reactions. Also, beading of the corneal nerves is common, and may be a helpful diagnostic sign.

In all LL patients and in BL with extensive disease, wide dissemination of the infection is the rule. In the upper respiratory tract involvement is from the tip of the nose through the vocal cords, manifesting as rhinitis, septal perforation, nasal collapse and hoarseness. As judged by elevated FSH and LH levels, testicular involvement with loss of testosterone production is common in LL men, less so in BL men, and is clinically manifested by complaints of impotence and infertility, and, on examination, by atrophy. Involvement of liver, spleen, peripheral lymph nodes, and bone marrow is common, but clinically evident organ injury is unusual. With effective chemotherapy, chronic disability from ocular or upper respiratory tract involvement is less common than previously, but has not disappeared. Ophthalmologists and otolaryngologists are still vital to evaluate and treat acute changes, and to prevent chronic changes in patients with leprosy.

Pregnancy and Postpartum

Pregnancy is said to be a precipitating factor for leprosy in 10%–25% of women patients, presumably because of altered immunity. When pregnant, LL and BL patients are predisposed to develop ENL, but in the postpartum period, they are predisposed to develop reversal reactions, putatively due to reduced immunity in the former and restored immunity in the latter.32 Untreated lactating BL and LL patients have viable bacilli in their milk, but no increased risk of disease transmission has been identified in infants ingesting such bacilli.33 Dapsone in mother's milk may produce hemolysis in the baby.

Acquired Immunodeficiency Syndrome or AIDS

In contrast to the high incidence of tuberculosis and M. avium-intracellulare infections in AIDS or HIV patients, leprosy has not been regarded as an opportunistic infection in these individuals, perhaps as a consequence of M. leprae being an obligatory intracellular parasite. For example, in one study AIDS or HIV did not appear to influence disease expression (tuberculoid versus lepromatous) or the frequency of reactional states, but was a risk factor for recurrent DTH reactions.34 However, recent reports of leprosy presenting as DTH reactions in the setting of highly active antiretroviral therapy (HAART) (eFig. 186-6.10) suggest that the current views may need revision.35

Relapsing Leprosy

“Multibacillary” patients who are noncompliant or who develop drug resistance are prone to relapse. Such individuals present in several ways, including (1) a reprise of their initial presentation, (2) florid dermatofibroma-like lesions (histoid lesions), (3) a reactional state, and (4) a clinical state of higher resistance than their initial presentation, for example, an initially LLs individual having BL or even BT disease. LLp patients do not develop reversal reactions.

Reactional States

The reactional states of leprosy are distinctive, tissue destructive, inflammatory processes that are putatively immunologically driven. They greatly increase the morbidity of the disease and, because of the experience required for optimal patient care, justify leprology as a clinical subspecialty. When present, a reactional state is superimposed upon the underlying granuloma, but the reactional state usually dominates the clinical picture. Too often, the reactional states are dismissed as complications of treatment, but they may occur before treatment is initiated or after it has been completed. They distress the patient who correctly complains, “I did every thing the doctor advised, but I got worse.”

Reversal Reaction (Jopling's Type I Reaction)

Reversal reactions are particularly common in BL patients, but are not rare in LLs, BB, or BT.36 Reversal reactions are supported by substantial evidence to be a delayed-type hypersensitivity (DTH) response and are also known as DTH reactions. Though theoretically patients may upgrade to a more-resistant granulomatous posture, remain unchanged, or downgrade to a less-resistant posture. Downgrading is rarely if at all ever observed, and type I reactions are associated with reversal (upgrading). Therefore, reversal reaction is often synonymous with “upgrading” resulting in improved CMI or DTH “reactions.” LLp patients do not develop DTH reactions.

Clinically, DTH reactions are characterized by the abrupt conversion of previously torpid plaques to tumid lesions, and new tumid lesions arising in clinically normal skin with or without an abrupt onset of neuritis. A purplish dusky erythematous color is characteristic (eFigs. 186-6.10 and Figs. 186-7A and 186-7B). Morphologic variants include annular, concentric and eczematous changes (eFigs. 186-7.1, 186-7.2, and 186-7.3). Lesions are rarely solitary, as can happen in BT upgrading to TT, often multiple, and occasionally myriad, as in BL or LLs upgrading to BT (eFig. 186-6.10). Iritis and lymphedema (eFig. 186-7.4) (elephantiasis graecorum) may be concomitant changes. Neuritis also ranges from mild to severe, and is potentially disastrous, particularly if involving multiple nerves. For example, in LL commonly, and in BL occasionally, a withering away of the type C pain fibers results in diminished pain perception and in severe cases may result in loss of the protective pain sensation. This may be referred to as a “stocking glove pattern of sensory impairment.” Motor loss with nerve involvement in addition to loss of sensation may occur in distal arms and legs.

Patients often present with DTH reactions, and DTH reactions occurring soon after presentation and the initiation of treatment may well have been DTH reactions from the beginning.37 Presumably, the increased prominence of signs and symptoms motivate patients to seek medical attention. Most common in the first year of treatment, DTH reactions may occur 7 years or longer after starting therapy, and well after treatment has stopped. The diagnosis of a DTH reaction is primarily clinical, but histologic confirmation, if available, should be sought.

Reversal Reaction Histology

Biopsies of reversal reaction tissues, when compared with prereactional biopsies in the same patient, occasionally do not differ. However, the most common change is edema (eFig. 186-7.5). Other common changes are enhanced epithelioid differentiation of macrophages, increased lymphocytes, Langhans-type and foreign-body giant cells often mixed together, epidermal thickening, and, occasionally, enhanced bacteriolysis (eFigs. 186-7.5–186-7.6). Nerve histology may change rapidly in a reversal reaction, in which nerves may be destroyed by a granulomatous infiltrate (eFig. 186-7.7). Edema and well-developed epithelioid tubercles associated with AFB, plasma cells, or a mixture of Langhans and foreign-body giant cells should arouse suspicion of a reversal reaction.

Erythema Nodosum Leprosum (Jopling's Type II Reaction)

ENL occurs most often in LL, in up to 75% of cases, but is not rare in BL patients. ENL is not erythema nodosum occurring in leprosy; it is a leprosy-specific response, which has some clinical and histologic features in common with erythema nodosum. It may occur before, during, or after chemotherapy. Excluding untreated patients who present because of ENL, the median time of onset of ENL is close to 1 year after onset of treatment. Clinically, this reaction is characterized by crops of painful and tender, bright pink, dermal and subcutaneous nodules in clinically normal skin, in association with fever, anorexia, and malaise. Arthralgias and arthritis are more common in ENL than are neuritis, adenitis, orchitis/epididymitis, or iritis, but each may rarely be the initial presentation. Involvement of both upper and lower extremities is the rule and facial lesions occur in half the patients. Lesions may be targetoid, vesicular, pustular, ulcerative, or necrotic (Fig. 186-8 and eFigs. 186-8.1, 186-8.2, 186-8.3, 186-8.4, and 186-8.5). A neutrophilic leukocytosis is often present, occasionally leukemoid in degree. Severe episodes can be associated with an abrupt fall in hemoglobin level, up to 5 g/dL, easily mistaken for dapsone-induced hemolysis. The improvement in response to thalidomide is dramatic in more than 90% of patients, perhaps qualifying as a diagnostic criterion. When leprosy presents as ENL, there may be few or no stigmata of the underlying disease. ENL may be precipitated by pregnancy or pyogenic infections.

Although episodes of ENL may be sporadic, in the more severely involved patients, episodes can be frequent to virtually unremitting. In the latter, brawny induration of the anterior thighs and preaxial portion of the arms is characteristic, perhaps a reversible fibrosis. The course of ENL is often prolonged, the median duration of anti-inflammatory treatment being approximately 5 years. If the diagnosis of ENL is considered, it is usually not difficult, as the clinical and histologic features and the response to thalidomide therapy are highly characteristic.

ENL Histology

A “bottom-heavy” pattern is a low-power feature of most ENL lesion, showing a gradient of inflammatory cells, scant in the papillae and heavy in the deep dermis or subcutis (eFig. 186-8.6). An uncommon alternative histology is a pan-dermal infiltrate with marked edema of the papillary dermis (eFig. 186-8.7). In ENL lesions, neutrophils are the “signature” cells, but may not be found if older lesions are sampled. The extent of the neutrophil infiltrate is highly variable, being so dense as to form a small abscess (eFig. 186-8.8), or very scarce. Other common features are an increase in lymphocytes, epidermal thickening, lobular panniculitis, and fibrosis. An uncommon but not rare finding is vasculitis (eFig. 186-8.9) that appears focal in distribution.

Lucio's Phenomenon

This is an often dramatic onset of hemorrhagic infarcts on the skin, most prevalent in Mexico and the Caribbean region and restricted to patients with Latapi's lepromatosis (Lucio's leprosy).

When fully developed, Latipi's lepromatosis features diffuse infiltration of the skin, as well as a purplish suffusion of the hands and feet, telangiectatic mats or eruptive telangiectasias, nasal septum perforation, total alopecia of eye brows and eye lashes, and often a stocking glove pattern of sensory impairment. Firm subcutaneous nodules are palpable but not visible. Ocular sparing is the rule.

Lucio's phenomenon usually occurs after Latapi's lepromatosis is well developed and, with few exceptions, before treatment is initiated. Hemorrhagic infarcts, arising in crops, have serrated margins characteristic of septic infarcts and are painful but not tender (eFigs. 186-8.10 and 186-8.11). Lesions usually crust and may heal with scarring. Some lesions are bullous. Ulceration is common, especially below the knees. Lesions vary in size and extent, ranging from a few small lesions on the ankles to many large ulcerations that are life threatening. With dapsone alone, lesions may worsen, but in our experience, with one exception, new lesions ceased within 1 week of beginning rifampin.

Lucio's Phenomenon Histology

Immunopathology and Immunology

Cellular Immunity

Antibody Immunity

Laboratory Tests

Polymerase chain reaction (PCR) testing for diagnosis of leprosy is not used in clinical practice, as in AFB-negative BT tissue a positive signal occurs less that half the time. Most laboratory abnormalities occur in LL or extensive BL disease. Hyperglobulinemia is the most common, giving an elevated sedimentation rate. A biologic false-positive serologic test for syphilis, anemia of chronic disease, and mild lymphopenia are also common. Clinically insignificant antiphospholipid antibodies are present in 50% of LL patients, and may give rise to a lupus anticoagulant or agglutination of sheep erythrocytes (Rubino factor).53 If sought, the stained smear of the buffy coat shows bacilli up to 105/mL. Elevated serum lysozyme and angiotensin-converting enzyme values reflect the extensive accumulation and activation of macrophages synthesizing these proteases. Proteinuria, not uncommon, is associated with a focal glomerulonephritis, seen mostly in patients with ENL. Low testosterone levels, accompanied by high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) values indicating testicular disease, occur in a majority of men with LL, but in a minority of men with BL.

A firm diagnosis of leprosy requires demonstration of a consistent peripheral nerve abnormality or the demonstration of AFB in tissues.

In nonendemic areas the diagnosis is missed only because the possibility of leprosy is not considered. There is no test to exclude leprosy.

Because M. leprae does not grow in cell-free media, demonstration of mycobacteria by their acid-fast property is used most commonly in diagnosis. AFB in tissue sections are best shown by carbolfuchsin staining, using modifications of the Ziehl–Neelsen method, collectively called Fite–Farraco stains. M. leprae, like Nocardia species, is only weakly acid-fast. In smears, either the Ziehl–Neelson method or auramine–rhodamine staining with fluorescent microscopy is satisfactory. Because of characteristic clinical and histologic changes, positive specification of M. leprae is rarely required. The presence of M. leprae in nerves or the presence of epithelioid cell granulomas within nerves are diagnostic, while characteristic histologic changes may suggest or corroborate the diagnosis of leprosy.

The common complications of leprosy arise from peripheral nerve injury, venous insufficiency, or scarring. Approximately one-quarter to one-third of newly diagnosed patients with leprosy have, or will eventually have, some chronic disability secondary to irreversible nerve injury, usually of the hands or feet, or from eye involvement. Exposure keratitis may result from a variety of factors including a dry eye, corneal insensitivity, and lagophthalmos. This keratitis and the anterior chamber lesions (including involvement of iris, sclera or corneal nerves) may result in blindness. Venous insufficiency, secondary to endothelial involvement of deep vein valves, leads to stasis dermatitis and leg ulcers. Destruction of joints (Charcot joints) may occur due to loss of the protective pain sensation. Sympathetic nerve involvement results in decreased hidrosis, leading to dry palms and soles. This in combination with repetitive cycles of skin injury from diminished protective pain results in hyperkeratosis, fissuring and bacterial superinfection. Collapse of the nose in LL is from the contracture of the scar tissue, which has replaced the bone and cartilage. Uncommon complications of Lucio's phenomenon include septicemia from extensive ulceration and contracture secondary to scar formation.

Nerve injury leading to loss of muscle innervation may lead to weakness. Repetitive cycles of injury and bacterial superinfection, permitted by loss of protective pain sensation, are the sources of severe tissue destruction in leprosy. Contracture, secondary to muscle weakness or scar formation, may produce further deformity. Management and prevention of the problems arising from nerve injury may require the skills of orthopedic surgeons, ophthalmologists, podiatrists, plastic surgeons, physical therapists, orthotists, and/or occupational therapists.

The only leprosy patients who will cure themselves without therapy are those with TT, or BT patients who upgrade to TT. Otherwise the disease will be progressive, with morbidity due to nerve injury and/or superimposed reactional states. Treatment arrests much of disease activity but the stocking-glove pattern of sensory impairment may progress. Peripheral neuritis of resent onset may improve with corticosteroid treatment. Like the postpolio syndrome, late arising sensory impairment is sometime seen and is difficult to understand and to manage.