# 69 - 184 Leprosy

### 184 Leprosy

Jan H. Richardus, Hemanta K. Kar, 

Zoica Bakirtzief, Wim H. van Brakel

Leprosy
Leprosy, also referred to as Hansen’s disease, is a chronic infectious 
disease caused by Mycobacterium leprae. The clinical manifestations 
are largely confined to the skin, peripheral nervous system, eyes, and 
upper respiratory tract. The differing immune responses to M. leprae 
result in a spectrum of disease ranging from tuberculoid to leproma­
tous leprosy. M. leprae has a predilection for peripheral nerves, and 
immunologically mediated reactional states can cause nerve damage 
to the face, arms, and legs; this damage often results in disability, 
which in turn can lead to stigma and social exclusion. The physical 
disfigurement that accompanies leprosy has left marks on society that 
have endured long after the disease’s disappearance in many countries. 
In everyday language, leprosy has become a metaphor for a horrible 
condition that warrants social exclusion. Leprosy is a neglected disease 
and is often thought no longer to exist. However, 174,087 new cases 
from 182 countries were reported in 2022. A general lack of awareness 
among both the public and medical practitioners often delays diagnosis 
and treatment and thus results in irreversible impairments. Early diagnosis 
and treatment of leprosy and leprosy reactions can cure the disease and 
prevent most chronic complications.
■
■ETIOLOGY
M. leprae is an obligate, intracellular, acid-fast staining, rod-shaped 
bacterium, measuring 1–8 μm in length and 0.3 μm in diameter. 

M. leprae mostly appears irregularly stained and fragmented or granu­
lar, in which case the organism is usually considered to be dead. The 
few bacteria that are brightly and uniformly stained are thought to be 
solid, viable bacilli. The morphologic index is a measure of uniformly 
stained solid bacilli on slit-skin smear examination and is calculated 
as the percentage of viable bacilli among the total number of bacilli 
counted under oil-immersion microscopy. On slit-skin smear exami­
nation at the lepromatous end of the disease spectrum, M. leprae is pre­
dominantly found in clumps or globi within macrophages (lepra cells). 
Inside these cells, M. leprae multiplies in unrestricted fashion, and hun­
dreds of bacilli may be present; the organisms are arranged in parallel 
arrays placed side by side as a result of the presence of surface lipids 
(glial substances). The bacteriologic index is a logarithmic-scaled mea­
sure of the density of bacilli of all forms found in the dermis upon slitskin smear examination, varying from 0 to 6+ (with or without globi) 
from the tuberculoid to the lepromatous end of the disease spectrum. 
The bacteriological index falls an average of 1 log unit per year with 
multidrug therapy. M. leprae infects mainly macrophages and Schwann 
cells. It has never been grown in artificial media. Reproduction occurs 
by binary fission, and the organism grows slowly (over 12–14 days) 
in the footpads of mice. The temperature required for survival and 

proliferation—between 27°C and 30°C—explains the greater impact of the 
disease on surface areas such as the skin, peripheral nerves, testicles, 
and upper airways, with less inner visceral involvement. M. leprae 
remains viable for 9 days in the environment.
PART 5
Infectious Diseases
Ultrastructural Characteristics of M. leprae 
Electron micros­
copy reveals that M. leprae has a cytoplasm, plasma membrane, cell 
wall, and capsule. The cytoplasm contains structures common in grampositive microorganisms. The plasma membrane has a permeable lipid 
bilayer containing interacting proteins—the protein surface antigens. 
Similar to that of other mycobacteria, M. leprae’s cell wall, which is 
attached to the plasma membrane, is composed of peptidoglycans 
bound to branched-chain polysaccharides; these peptidoglycans are 
arabinogalactans, which support mycolic acids, and lipoarabinoman­
nan (LAM). The capsule—the outermost structure—contains lipids, 
particularly phthiocerol dimycocerosate and phenolic glycolipid (PGL-1), 
which has a trisaccharide bound to lipid by a molecule of phenol. 

Because this trisaccharide is antigenically specific for M. leprae, its 
detection is helpful in serologic diagnosis of leprosy.
Genome of M. leprae 
 Comparative analysis of the genomics 
of single-nucleotide polymorphisms indicates that four distinct 
strains of M. leprae originated in East Africa or Central Asia. A 
mutation spread to Europe and subsequently underwent two separate 
mutations that were then followed by spread to West Africa and the 
Americas. The genome of M. leprae is circular. Its estimated molecular mass 
is 2.2 × 109 Da, with 3,268,203 base pairs and a guanine-plus-cytosine 
content of 57.8%.
Culture Difficulties 
Compared to the genome of Mycobacterium 
tuberculosis, that of M. leprae underwent reductive evolution, result­
ing in a smaller genome rich in inactive or entirely deleted genes. 
This reductive evolution, gene decay, and genome downsizing all may 
explain the unusually long generation time and may account for the 
inability to culture the leprosy bacillus in artificial media. As a result, 
propagation of M. leprae has been restricted to animal models, includ­
ing the armadillo and normal, athymic, and gene-knockout mice. 
These systems have provided the basic resources for genetic, metabolic, 
and antigenic studies of the bacillus. Growth of M. leprae in mouse 
footpads also provides a tool for assessing the viability of the bacteria 
and testing the drug susceptibility of clinical isolates.
Immunologic Properties of M. leprae 
M. leprae induces both 
humoral and cell-mediated immune responses. The immunogenic 
components of M. leprae include polysaccharides and proteins. Poly­
saccharide components induce mainly a humoral immune response, 
whereas protein components induce both humoral and cell-mediated 
immune responses. The immunogens in M. leprae form two distinct 
groups: cytoplasmic antigens and antigens from the mycobacterial cell. 
As mentioned above, a species-specific phenolic glycolipid, PGL-1, 
has been identified in M. leprae. Other varieties of M. leprae antigens 
identified with monoclonal antibodies include antigens of 18, 28, 7, 
14, 36, 65, and 70 kDa that may possibly induce an immune response.
Mycobacterium lepromatosis 
In 2008, a new mycobacterial species, 
M. lepromatosis, was isolated from patients with a special type of dif­
fuse lepromatous leprosy known as diffuse leprosy of Lucio and Latapí. 
This clinical variety of leprosy is found mainly in Mexico and Central 
America. M. lepromatosis is very similar to M. leprae microbiologically 
and clinically. Microbiologically, both species are acid-fast and noncul­
tivable and preferentially infect skin and peripheral nerves. Clinically, 
differentiation of M. lepromatosis from M. leprae in individual patients 
is not diagnostically necessary since both organisms respond well to 
the same antimycobacterial regimens.
■
■EPIDEMIOLOGY
Incidence, Prevalence, and Disability 
The true incidence 
of leprosy is difficult to establish because the figure is very low and 
because the initial signs and symptoms are often insidious, and thus 
not all cases are detected as they occur. In 2022, as stated earlier, 
174,087 new cases were reported to the World Health Organization 
(WHO) from 182 countries. New case detection per year is commonly 
used as a proxy for incidence, but operational factors, such as the inten­
sity of case detection, the use of surveys, the use of contact tracing, the 
level of community awareness, and the quality and availability of health 
care, have a profound effect on case detection rates. In nonendemic 
countries around the world, leprosy is often misdiagnosed simply 
because it is not considered.
The registered prevalence of leprosy is defined as the number of 
patients receiving treatment at a point in time (usually at the end of a 
calendar year). The registered prevalence is a proxy measure for true 
prevalence, which would include existing cases that have not yet been 
detected. The two factors that determine the registered prevalence are 
the new case detection rate and the duration of treatment; changes in 
either factor will affect the registered prevalence.
The WHO leprosy disability grading system scores patients accord­
ing to the presence of disabilities of the eyes, hands, and feet. For the

900,000
800,000
700,000
600,000
500,000
400,000
300,000
200,000
100,000

FIGURE 184-1  Global trend in leprosy new-case detection, 1990–2022.
hands and feet, grade 0 means no anesthesia and no visible impair­
ment; grade 1 signifies anesthesia but no visible impairment; and grade 
2 indicates visible impairment. For the eyes, grade 0 signifies no eye 
problems due to leprosy and no evidence of visual loss; grade 1 signifies 
eye problems due to leprosy without severe effects on vision; and grade 
2 indicates severe visual impairment (vision score worse than 6/60; 
inability to count fingers at 6 meters) and also includes lagophthalmos, 
iridocyclitis, and corneal opacities. The sum score for these six body 
sites is called the Eye-Hand-Foot (EHF) score and is used as an overall 
indicator of the impairment status of a person with leprosy. Leprosyrelated grade 2 disability is usually reported as the proportion of people 
with such disability at any site among patients newly diagnosed with 
leprosy in a specific year.
The global trend in new case detection since 1990 is presented in 
Fig. 184-1. The trend was remarkably static up to the year 2001, with 
a peak around the year 2000; fell dramatically between 2001 and 2005; 
and has leveled off from 2006 until 2016. Since 2017, a continuous 
decline has been observed, but the figures for 2020 and 2021 are unreli­
able due to underreporting during the COVID-19 pandemic. The most 
important factor contributing to the fast downward trend after the year 
2000 was the decline in leprosy control activities following the decla­
ration by the WHO in 2000 that leprosy was eliminated as a “public 
health problem.” Elimination was defined as a prevalence of <1 case per 
10,000 population at the global level. The decline in new case detection 
since 2016 to below 200,000 cases per year indicates that transmission 
of M. leprae is becoming less and that elimination of leprosy could 
become possible in the next 25 years or so.
Sex, Age, and Geographic Distribution 
Approximately 40% 
of all reported leprosy patients are women, but the low proportion in 
some countries raises concerns about underdiagnosis in women due to 
poor access to health services, illiteracy, low status, and other cultural 
factors. The age-specific incidence often shows a bimodal pattern, with 
peaks in the teenage years and in adulthood. Around 8% of all newly 
detected cases are found in children (<15 years of age), a measure that 
is often taken as an indicator of continued (recent) transmission. 
Leprosy is rare among children <5 years of age. Around 5% of all 
patients have a grade 2 disability.
There are large variations among world regions and countries in 
new case detection rates. Approximately 80% of global new case detec­
tion is reported from India, Brazil, and Indonesia. There are also dis­
tinct geographic variations within countries, with differences between 
urban and rural communities and clustering of cases at the village or 
neighborhood level. Geographic variations can be due to differences 
in health service provision, socioeconomic development, isolation, 

and poverty. Figure 184-2 depicts the geographic distribution of new 
leprosy cases in 2022.
Transmission 
Understanding of the transmission of M. leprae 
is limited. The existing evidence is largely circumstantial because of 
the long incubation period from exposure to disease, the inability to 
culture M. leprae, and the difficulty of diagnosing both infection and 
early disease. M. leprae organisms can be shed in large numbers from 
the mouth and nose of patients with untreated multibacillary leprosy 
(droplet infection) and sometimes from damaged skin, but it is unclear 
whether patients with paucibacillary leprosy can spread the bacillus. 
There is evidence for transmission between humans and—in southern 
U.S. states—for zoonotic transmission through wild armadillos. The 
main route of entry into the body is assumed to be the respiratory tract, 
but in patients with wounds or tattoos, transmission through the skin 
also is possible.
CHAPTER 184
Leprosy
Reservoirs of Infection 
It is assumed that humans are the main 
reservoir of infection for M. leprae. The armadillo is also a reservoir 
for human infection. Certain species of monkeys and red squirrels 
are infected with M. leprae in the wild, but there is no evidence of 
transmission to humans through contact with these animals. Evidence 
is weak for the potential of water and soil as environmental sources of 
M. leprae. The higher incidence rate of leprosy among household con­
tacts of multibacillary cases than among those of paucibacillary cases 
suggests that multibacillary cases represent an important reservoir for 
undetected and untreated cases in the community; that is, a prolonged 
period between the onset of signs of leprosy and treatment due to a 
delay in diagnosis and initiation of multidrug therapy increases expo­
sure in the community. Persons with subclinical leprosy are likely to 
be a main source of infection, given that multidrug therapy for clinical 
leprosy apparently has not made an impact on transmission.
Incubation Period, the Role of Contacts, and Genetic Sus­
ceptibility 
The incubation period of leprosy is estimated to range 
from 2 to ≥10 years. The incubation period for multibacillary leprosy 
appears to be longer (5 to ≥15 years) than that for paucibacillary lep­
rosy (~2–5 years). Poverty-associated factors such as low level of edu­
cation, poor hygiene, and food shortages have been identified as risk 
factors for leprosy, but the most important risk factors are associated 
with intimacy and duration of contact with a leprosy patient, in par­
ticular with an index case with multibacillary leprosy, and the intensity 
of contact with and physical distance from the index patient. Increasing 
evidence from studies in twins and from observational studies supports 
host genetic susceptibility to leprosy. Ongoing studies are exploring the

New leprosy cases, 2022 – Nouveaux cas de lèpre en 2022

1–10 
11–100 
101–1000
1001–10,000
>10,000
No data – Aucune donnée
FIGURE 184-2  Geographic distribution of new leprosy cases, 2022. (Reproduced with permission from Global leprosy (Hansen disease) update, 2022: new paradigm-control 
to elimination. Wkly Epidemiol Rec 98:409, 2023.)
PART 5
Infectious Diseases
mechanism underlying genetic susceptibility to leprosy and its clinical 
manifestations.
■
■PATHOGENESIS
Whatever the route of M. leprae’s entry into the human body, the 
pathogenic process usually starts in the peripheral nerves. Once bacilli 
are engulfed by Schwann cells, the histopathologic changes in nerve 
and skin—and thus the type of leprosy that develops—depend on the 
immunologic resistance of the person infected, in particular on the 
cell-mediated immune (CMI) response to the bacillus and its antigens.
Ridley-Jopling Classification of Leprosy 
In 1962, Ridley and 
Jopling described five overlapping categories of leprosy: tuberculoid 
(TT), borderline tuberculoid (BT), mid-borderline (BB), borderline 
lepromatous (BL), and lepromatous (LL). An early clinical manifes­
tation is recognized and referred to as indeterminate leprosy (IL). 
Immunologic resistance is strong at the tuberculoid end of the spec­
trum, gradually diminishes through the borderline spectrum, and is 
weakest in lepromatous leprosy. The LL and TT types of leprosy are 
relatively stable, with little or no change in clinical disease expression 
over time, while the BL, BB, and BT types are unstable both clinically 
and immunologically. Further distinction indicates that subpolar types 
of TT and LL leprosy (TTs and LLs) are less stable than polar types 
(TTp and LLp). The immune reaction depends on predisposing genetic 
factors and the extent of exposure to M. leprae. The host tissue’s reac­
tion and related damage are largely due to delayed hypersensitivity. In 
response to the presence of M. leprae, a granuloma is formed either 
by macrophage–lymphocyte interaction when there is immunity or 
otherwise by macrophages only. The formation of a granuloma is pre­
ceded by a stage of infiltration by lymphocytes alone, as is seen in IL. 
Because of the strong immune response toward the tuberculoid end of 
the spectrum, macrophages, along with many lymphocytes, become 
fixed epithelioid cells, and groups of these cells become giant cells. The 
tuberculoid granuloma leads to nerve destruction resulting in anes­
thesia and muscle weakness. The cellular response is less focal and less 
destructive in the borderline portion of the spectrum; consequently, 
there is less damage to nerves and few bacilli are present. In BL leprosy, 
there are macrophage granulomas along with lymphocytes, but little 
nerve damage and more bacilli. In LL leprosy, bacilli multiply within 

Schwann cells and perineural cells. Liberated bacilli from these cells are 
engulfed by histiocytes, becoming wandering macrophages and travel­
ing throughout the body to other nerves and tissues via blood, lymph, 
and tissue fluids. In addition, there are diffuse lepromas in LL leprosy 
that consist of histiocytes and/or macrophages, with very few lym­
phocytes and plasma cells. The bacilli are packed within macrophages 
called globi and outside macrophages either singly or in small groups.
WHO Simplified Clinical Classification of Leprosy 
RidleyJopling classification requires clinical and pathologic expertise that 
does not exist in many settings. The WHO has therefore introduced 
a simplified classification system based on slit-skin smear: patients 
with negative slit-skin smear results at all body sites are classified as 
having paucibacillary leprosy, whereas patients with positive smears at 
any body site are classified as having multibacillary leprosy. However, 
because slit-skin smear facilities are not available or dependable in 
many countries, most leprosy control programs use clinical criteria 
only for classifying leprosy and deciding on the appropriate treatment 
regimen for individual patients. In this circumstance, paucibacil­
lary leprosy is defined as one to five skin lesions and no or only one 
involved peripheral nerve, while multibacillary leprosy is defined as six 
or more skin lesions and/or more than one involved peripheral nerve.
■
■CLINICAL MANIFESTATIONS
Leprosy is a disease affecting mainly the skin, cutaneous and peripheral 
nerves, mucous membranes, and, less commonly, other sites such as 
joints, lymph nodes, eyes, and testes. Other systemic manifestations 
may occur, particularly in BL and LL disease, with or without leprosy 
reactions. Most dermal and cutaneous nerves feeding skin lesions 
are affected—e.g., the supraorbital, great auricular, radial cutaneous, 
infrapatellar, superficial fibular, and sural nerves and the cutaneous 
nerves of the thigh. The peripheral nerves involved include the ulnar, 
median, radial (in upper limbs), lateral popliteal, and posterior tibial 
(in lower limbs). The cranial nerves commonly involved are the tri­
geminal and facial.
Indeterminate Leprosy (IL) 
This early clinical type manifests 
as one or a few hypopigmented or faintly erythematous, ill-defined 
to well-defined macular lesions measuring 1–5 cm in diameter. These 
lesions invariably occur on the external aspects of the limbs, buttocks,

FIGURE 184-3  Tuberculoid (TT) leprosy. Hypopigmented macular lesion with a welldefined edge and loss of fine-touch sensation. (From Dr. H. K. Kar, with permission.)
and face, with mild to moderate impairment of touch and/or thermal 
sensations. There is no thickening of the corresponding cutaneous 
and peripheral nerves. IL is often, but not always, the first clinical 
sign of leprosy. This type either heals spontaneously or progresses to 
a determinate form of the disease (TT, BT, BB, BL, or LL), depending 
on CMI status.
Tuberculoid (TT) Leprosy 
TT leprosy (Fig. 184-3) presents 
either as a well-defined, hypopigmented macule or as a raised, 

erythematous/brown/copper-colored plaque with a well-defined edge. 
The lesions may be found on any part of the skin and are characterized 
by complete loss of fine touch and temperature sensations over their 
surface. Skin lesions are single or few (up to three) in number and can 
be of any size, but they seldom measure >10 cm in diameter. In plaquetype lesions, the raised clear-cut edge often slopes inward to a flattened 
and sometimes hypopigmented central area, acquiring an annular con­
figuration. The skin surface of both macular and plaque lesions is dry, 
hairless, and anesthetic because of destruction of underlying superficial 
cutaneous nerves. Larger corresponding cutaneous nerves are thick­
ened in a limited number of cases. On the face, sensory impairment 
may be difficult to demonstrate because of the generous and bilateral 
supply of sensory nerve endings. Autonomic nerve damage within the 
lesion is responsible for surface dryness and loss of sweating over the 
lesion. A solitary peripheral-nerve trunk in the vicinity of a lesion may 
be thickened, with sensory loss of the area supplied and with or with­
out motor disfigurement. On slit-skin smear examination, no acid-fast 
bacilli (AFB) are normally found. The lepromin skin test is strongly 
positive, signifying good host CMI status.
Borderline Tuberculoid (BT) Leprosy 
BT leprosy (Fig. 184-4) 
is characterized by either macular or plaque-type lesions numbering 
three to nine or more and asymmetrically located on any part of the 
body, with variable sizes and contours. The margins of the lesions range 
from poorly defined to well defined; sometimes both forms of margin 
are seen in one lesion. There may be smaller satellite lesions around 
a larger one, especially on sides where the margin is less defined; this 
characteristic indicates downgrading of the lesion from TT to BT 
leprosy. The edges of plaque lesions may slope outward in contrast to 
TT lesions, which slope inward; plaques may gradually fade outward 
and eventually blend into normal-looking skin. Loss of sensation is 
less intense than it is in TT lesions and dryness on the surface less 
conspicuous. Several peripheral nerves are likely to be enlarged in an 
asymmetrical pattern, with sensory and motor deficits. One of the 
most striking features of BT leprosy is susceptibility to a type 1 leprosy 
reaction (T1R; see below) that exacerbates skin lesions and/or periph­
eral nerves. If not diagnosed and treated early, disease in these patients 
tends to downgrade across the spectrum to BB, BL, or LLs leprosy, with 
an increasing bacteriologic index and a regressed CMI response caus­
ing nerve damage along the way. Slit-skin smears show bacteriologic 
indices varying from negative to 1+.

FIGURE 184-4  Borderline tuberculoid (BT) leprosy. Macular lesion with irregular, 
moderately defined edge and satellite lesion, with loss of sensation. (From Dr. W. H. 
van Brakel, with permission from NLR.)
Mid-Borderline (BB) Leprosy 
This form of leprosy is unstable. 
Many cases downgrade toward BL and LL disease, especially if not 
treated. There are multiple plaque lesions and, not infrequently, macu­
lar lesions; the lesions are of various shapes and sizes, are bilateral, and 
usually occur in a more or less symmetrical distribution. In annular 
lesions, the inner edge is well demarcated and “punched out,” and the 
outer edge is ill defined and merges with normal-looking skin. The 
surface of the lesions is moderately shiny, and the central area looks 
pale. There is minimal loss of sensation over the lesions. Nerve dam­
age is variable in BB leprosy. Many nerves may be thickened, and this 
effect may be asymmetrical. BB leprosy is not commonly observed and 
rapidly changes its spectrum—rarely to BT leprosy but more often to 
BL disease. The lepromin test is negative. Slit-skin smears of lesions 
show a moderate number of AFB (2+ to 3+).
CHAPTER 184
Leprosy
Borderline Lepromatous (BL) Leprosy 
In BL leprosy 

(Fig. 184-5), there are numerous bilateral, round or oval, macular, dif­
fusely infiltrated, erythematous or hypopigmented lesions with moder­
ately defined borders. The lesions are usually 2–3 cm in diameter, may 
have a coppery hue, and tend to become symmetrical. Some loss of 
FIGURE 184-5  Borderline lepromatous (BL) leprosy. Numerous diffusely infiltrated 
erythematous and hypopigmented macules, downgrading from borderline 
tuberculoid to lepromatous leprosy. (From Dr. C. L. M. van Hees, Department of 
Dermatology, Erasmus MC, University Medical Center, Rotterdam, the Netherlands, 
with permission.)

FIGURE 184-6  Lepromatous (LL) leprosy. Multiple nodules on ears and face and loss 
of eyebrows. (From Dr. K. Mponda, Department of Dermatology, Queen Elisabeth 
Central Hospital, Blantyre, Malawi, with permission.)
PART 5
Infectious Diseases
sensation may be detected, particularly over older lesions; however, no 
loss of sensation is observed over fresh lesions. With disease progres­
sion, papules, nodules, and plaques develop over the macular lesions. 
In untreated patients, new ill-defined skin lesions continue to develop. 
Widespread but asymmetrical thickening of peripheral nerves, with or 
without tenderness, leads to sensory and motor deficits. The lepromin 
test gives negative results, as it does in all degrees of lepromatous lep­
rosy. Slit-skin smear examination of lesions shows a bacteriologic index 
varying from 3+ to 4+.
Lepromatous (LL) Leprosy 
LL leprosy (Fig. 184-6) pres­
ents with innumerable bilateral, symmetrically distributed, diffusely 
indurated, erythematous, copper-colored or skin-colored patches or 
plaques. There is no loss of sensation over these lesions, which have a 
smooth, shiny surface. The lesions spread over the face, earlobes, ears, 
extensor aspects of the upper and lower extremities, back, and but­
tocks. Induration can readily be recognized when lesions are viewed 
tangentially under natural sunlight. The induration initially is of a 
finer type but gradually becomes coarse, and lesions then progress 
to papules, plaques, and nodules. Bilateral earlobe thickening and 
eyebrow loss occur. Coarse induration on the face sometimes results 
in gross skin folds that lead to an appearance referred to as “lion face,” 
particularly when associated with loss of eyebrows and thickening of 
earlobes. Of all cases of LL leprosy, 10–15% are of the polar type (LLp) 
from the time of lesion onset; the remaining cases downgrade from the 
untreated borderline spectrum to subpolar LLs leprosy. Patients with 
LLs disease develop nerve damage during the borderline stages. In LLp 
disease, involvement of peripheral nerves occurs late and is bilateral 
and symmetrical, with sensory loss in a “glove-and-stocking” distribu­
tion. Slit-skin smear examination shows a bacteriologic index of 4+ to 
6+ with globi.
SYSTEMIC INVOLVEMENT  In LL leprosy, AFB are found in the lymph 
nodes, spleen, liver, bone marrow, adrenal glands, smooth and striated 
muscles, tooth pulp, testes, oral cavity, nose, larynx, and eyes. Involve­
ment of the testes leads first to sterility and then to gynecomastia and 
impotence. Eye involvement includes corneal anesthesia; early on, this 
manifestation is due to bacillary infiltration of corneal nerves, while 

later it arises from damage to the ophthalmic division of the trigeminal 
nerve. In addition, eye involvement includes episcleritis, iridocyclitis, 
iris atrophy, cataract and glaucoma, lagophthalmos, corneal ulcer­
ation and perforation, and blindness. The nose is a portal of entry for 

M. leprae and is the earliest site of involvement in LL leprosy. Edema 
and mucosal thickening occur in the inferior turbinate and nasal 
septum, with crusting and epistaxis. Later, patients develop chronic 
rhinitis with loss of smell sensation. Septal perforation due to bony 
destruction, with typical saddle-nose disfigurement, is common in 
advanced LL disease. In late-stage LL leprosy, ulceration of the tongue, 
pharynx, hard and soft palates (leading to palate perforation), tonsillar 
pillars, and uvula occurs. In the hands, slow resorption sets in, starting 
from the distal end of the terminal phalanx and proceeding proximally 
to involve the middle and proximal phalanges.
HISTOID LEPROSY  Histoid leprosy is a rare form of LL leprosy in 
which waxy, shiny, firm, symmetrical or asymmetrical nodules and 
plaques are observed over normal-looking skin. Histologic examina­
tion of these lesions shows specific spindle-cell granulomas. Slit-skin 
smear examination reveals high bacteriologic and microbiologic indi­
ces without globi in most cases.
DIFFUSE LEPROSY OF LUCIO AND LATAPÍ  This rare form of nonnodu­
lar LL leprosy occurring in Mexico and Central America is character­
ized by diffuse shiny infiltration of the skin and widespread sensory 
loss. The skin looks waxy and has a shiny appearance (“lepra bonita,” 
or beautiful leprosy), with obvious diffuse induration of the earlobes 
and forehead as well as loss of eyebrows, sometimes eyelashes, and not 
infrequently all body hair. This form of leprosy can be complicated by 
an unusual reaction known as Lucio’s phenomenon (see below).
Primary Neuritic Leprosy 
In some countries, such as India and 
Nepal, primary neuritic disease is observed in 2–10% of all leprosy 
cases, with only peripheral nerve involvement and no skin lesions. 
Nerve thickening and sensory loss occur in the affected area, with or 
without a motor deficit. Primary neuritic leprosy, even though not 
described by Ridley and Jopling, can manifest at different points along 
the disease spectrum. For practical purposes, primary neuritic leprosy 
is classified as paucibacillary or multibacillary on the basis of the 
absence or presence of AFB in nerve biopsy sections or the number of 
thickened nerves (single or multiple).
■
■LEPROSY REACTIONS
Leprosy reactions are immunologic phenomena that occur before, dur­
ing, or after treatment. They are severe complications that need to be 
diagnosed and treated early to prevent nerve function impairment and 
subsequent disfigurement as well as blindness.
Type 1 Leprosy Reaction (T1R) 
T1R is a delayed hypersen­
sitivity reaction associated with sudden alteration of CMI status and 
leading to a shift in the patient’s position on the leprosy spectrum. 
This reaction is marked by infiltration of lesions by activated CD4+ T 
lymphocytes, especially T helper cells. T1R is also called a reversal reaction 
because of the upgrading of CMI status. T1R is usually observed in the 
borderline portion of the spectrum. Skin lesions are characterized by 
acute swelling and redness (Fig. 184-7). Nerves may be painful and 
tender because of neuritis, with consequent nerve damage and disfig­
urement. In the severe form of T1R, nerve abscesses may be formed. 
Loss of nerve function can be much less obvious than usual when 
it occurs without other signs of inflammation. This “silent neuritis” 
may lead to sensory and motor impairment in the hands, feet, and 
face. Arthralgia or arthritis sometimes occurs. Rarely, the patient may 
develop fever and malaise, tenosynovitis, and edema of the feet and 
hands.
Type 2 Leprosy Reaction (T2R) 
T2R, also known as ENL 
(erythema nodosum leprosum), is an immune complex–mediated 
syndrome (i.e., an antigen–antibody reaction involving complement) 
that causes inflammation of the skin, nerves, and other organs as well 
as general malaise. ENL is an example of a type III hypersensitivity 
reaction (Coombs and Gell classification) or Arthus phenomenon.

FIGURE 184-7  Type 1 leprosy reaction. Increased inflammation of existing lesions. 
(From Dr. W. H. van Brakel, with permission from NLR.)
This reaction occurs mostly during multidrug therapy but can also 
develop in untreated patients. Evanescent, pink-to-red, maculopapular, 
papular, nodular, or plaque lesions suddenly appear and are usually 
accompanied by constitutional symptoms like malaise and fever, with 
or without painful swelling in the joints (Fig. 184-8). These crops of 
skin lesions present on the outer aspects of the thighs, legs, and face. 
They are painful or tender and warm, blanch with light finger pres­
sure, and last for a few days. The lesions change in color from pink/
red to bluish and brownish after 24–48 h and turn dark in a week. 
Rarely, ENL lesions become vesicular, pustular, bullous, and necrotic 
and break down to produce ulceration (erythema nodosum necroti­
cans). The patient may have other associated signs such as lymph node 
enlargement, myositis, arthritis, synovitis, rhinitis, epistaxis, laryngitis, 
iridocyclitis, glaucoma, painful dactylitis, acute epididymoorchitis, 
nephritis and renal failure, hepatosplenomegaly, anemia, and—at a 
later stage—amyloidosis. Severe T2R may include swollen, painful, and 
tender nerve trunks with sensory and motor deficits.
Lucio’s Phenomenon 
Lucio’s phenomenon is observed in diffuse 
leprosy of Lucio and Latapí and may be a variant of erythema nodosum 
necroticans. Marked vasculitis and thrombosis of the superficial and 
deep vessels result in hemorrhage and infarction of the skin. Clinically, 
the skin reaction begins as slightly indurated, bluish-red, ill-defined, 
painful, and rarely palpable plaques with an erythematous halo, usu­
ally developing on one limb but sometimes on other areas of the body. 
The lesions are irregular or triangular. After a few days, they become 
purplish at the center; a central hemorrhagic infarct may develop with 
or without blister formation, and a necrotic eschar that detaches easily 
FIGURE 184-8  Type 2 leprosy reaction. Erythema nodosum leprosum, with pustular 
lesions. (From Dr. H. K. Kar, with permission.)

and leaves an ulcer of irregular shape may follow later. The ulcer heals, 
leaving a superficial scar. Patients remain afebrile throughout.

Nerve Function Impairment, Neuritis, and Disfigurement 

The terms nerve function impairment, nerve damage, neuropathy, and 
neuritis are often used interchangeably for the sensory, motor, and/
or autonomic nerve deficits that occur because of the pathologic pro­
cesses resulting from M. leprae infection of the nerve. Neuritis (nerve 
inflammation) in leprosy is usually a subacute, demyelinating, and 
unremitting event involving cutaneous nerves and larger peripheral 
nerves. “Silent neuritis” or “quiet nerve paralysis” is defined as progres­
sive sensory or motor impairment in the absence of symptoms such as 
pain, paresthesia, or tenderness of the nerve and with no obvious signs 
of leprosy reactions. Neuritis can occur at any time during leprosy but 
is more common and severe during leprosy reactions, mainly in T1R. 
Sensory and motor neuropathy can lead to secondary impairments in 
the upper and lower extremities, such as muscle atrophy, mobile- and 
fixed-joint contractures, bone absorption of digits, and cracks and 
wounds.
■
■DIAGNOSIS
Clinical Diagnosis 
Three cardinal signs indicate a diagnosis of 
leprosy. The diagnosis can be established when at least one of these 
three signs are present:
1.	 Hypopigmented or erythematous skin lesion(s) with definite loss or 
impairment of sensation: The clinical presentation of skin patches 
or plaques is diagnostic when it is associated with a definite loss or 
impairment of sensation (light touch, pain, and/or temperature). 
Diagnostic dilemmas arise in the indeterminate stage of leprosy 
because of variable loss of sensation and the presence of facial 
lesions (i.e., because the density of innervation in the face can com­
pensate for damage to certain nerve branches).
2.	 Involvement of the peripheral nerves, as demonstrated by definite 
CHAPTER 184
Leprosy
thickening with sensory impairment: Thickening of a peripheral 
nerve should be assessed by palpation of the affected nerve and 
comparison with the corresponding contralateral nerve. In mul­
tibacillary leprosy, thickening of nerves is often bilateral. Nerve 
tenderness is established by the application of mild pressure on the 
nerve during palpation with the fingertips. The peripheral nerves 
commonly palpated in a leprosy patient are the greater auricular, 
ulnar, radial, radial cutaneous, median, lateral popliteal, posterior 
tibial, sural, and superficial peroneal nerves.
3.	 A positive result for AFB in slit-skin smears, establishment of the 
presence of AFB in a skin smear or biopsy sample, or a positive 
result in a biopsy polymerase chain reaction (PCR).
Diagnostic Tools 
• 
TESTING OF SKIN SENSATION  Light-touch 
sensation is tested with cotton, wool, or a feather. Pain is assessed as 
the patient’s ability to distinguish between the sharp and blunt ends 
of a wooden or bamboo toothpick. Thermal sensation thresholds are 
assessed with computer-assisted sensory testing equipment.
SLIT-SKIN SMEAR  Normally a slit-skin smear is taken from four sites: 
the right earlobe, the forehead above the eyebrows, the chin, and 
the left buttock in men or the left upper thigh in women. The mate­
rial is stained with Ziehl-Neelsen reagent and examined with a light 
microscope. The bacteriologic index is determined with a standard 
logarithmic scale and graded from 0 to 6. The microbiologic index is 
determined as the percentage of solid, stained AFB.
SKIN BIOPSY  A skin biopsy is done to confirm the diagnosis of leprosy, 
to classify the disease, to support the diagnosis of reactions, and to deter­
mine cure after the completion of multidrug therapy. When macular 
lesions are suspected of reflecting IL, a biopsy sample should be taken 
from the middle of a lesion; with plaques, a sample should be obtained 
from the active indurated edge. When there are numerous skin lesions 
with different morphologies, more than one biopsy sample is required 
for proper evaluation of the disease spectrum. Identification of early 
lesions of leprosy by histopathologic techniques is enhanced by immu­
nochemical staining, which reveals the presence of M. leprae antigens.

PGL-1 ANTIBODY TEST  PGL-1 is a specific lipid on the M. leprae 
cell wall. A PGL-1 enzyme-linked immunosorbent assay (ELISA) has 
been used for serologic diagnosis of leprosy, yielding positive results 
in 90–95% of multibacillary cases and in 25–60% of paucibacillary 
cases. Using PGL-1 antigen and adopting an immunochromatographic 
technique, a rapid lateral-flow assay—the ML flow test—has been 
developed for detection of antibody to PGL-1. This assay gives posi­
tive results in 92–97% of patients with multibacillary leprosy and in 
32–40% of patients with paucibacillary disease. Recently, a quantitative 
UPC-LFA (upconverting phosphor lateral flow assay) test has become 
available, which has a higher specificity in paucibacillary disease.

LEPROMIN TEST  The lepromin (or Mitsuda) skin test measures cel­
lular immunity against lepromin. A bacillary suspension standardized 
by the number of inactivated M. leprae it contains is injected just 
under the skin. The reaction to lepromin is measured as induration in 

millimeters 3–4 weeks after intradermal inoculation. The result pro­
vides information about the ability of an individual’s T cells to respond 
to M. leprae and the likelihood of granuloma formation in that indi­
vidual. A negative lepromin test is generally seen in patients with LL or 
BL leprosy, indicating the lack of a protective cellular response.
GENE AMPLIFICATION (PCR) TECHNIQUE  Gene amplification signifi­
cantly enhances the detection of M. leprae, especially in bacteriologic 
index–negative leprosy and cases that do not fulfill the criteria for 
the cardinal signs of leprosy. The several PCR methods developed 
to amplify different gene stretches in M. leprae include conventional 
DNA-based PCR, reverse-transcription PCR, and multiplex PCR. As 
major genes for detection of disease targets, PCR uses M. leprae–specific 
genes encoding 36-kDa antigen, 18-kDa antigen, 65-kDa antigen com­
plex 85, 16S ribosomal RNA (rRNA), and repetitive sequences. These 
assays are sensitive to as few as 1–10 bacilli and yield positive results in 
60–75% of smear-negative cases. Multiplex PCR employing the genes 
encoding the repetitive element RLEP, SodA, and 16S rRNA can be 
used for early diagnosis and for the diagnosis of subclinical infection 
among household contacts.
PART 5
Infectious Diseases
Differential Diagnosis 
Leprosy is often diagnosed late, with a 
consequent increase in the risk of nerve damage and its ensuing dis­
abilities. The hypopigmented macules of leprosy must be differentiated 
from a variety of conditions, including pityriasis alba, vitiligo, pro­
gressive macular hypomelanosis, pityriasis versicolor, pityriasis rosea, 
postinflammatory hypopigmentation, sarcoidosis, post–kala-azar dermal 
leishmaniasis, and morphea. In the analysis of plaques and nodular 
lesions, conditions such as granuloma annulare, cutaneous sarcoidosis, 
cutaneous leishmaniasis, lupus miliaris disseminatus faciei, nodu­
lar histiocytosis, lupus erythematosus, cutaneous T-cell lymphomas 
(especially mycosis fungoides), and secondary syphilis should be kept 
in mind. ENL lesions must be differentiated from erythema nodosum 
of other etiologies, nodular vasculitis, and cutaneous polyarteritis 
nodosa. In the case of mononeuropathy lesions, diabetes, amyloidosis, 
and myxedema must be considered. With polyneuropathy lesions of 
acute onset, Guillain-Barré syndrome and toxic polyneuropathy must 
be given consideration.
Diagnostic Tools for Nerve Function Impairment 
All sen­
sory modalities, autonomic function, and motor function of motor 
nerves may be affected in leprosy to varying degrees. The modalities 
mediated by small unmyelinated fibers, such as pain and warm tem­
perature sensation and autonomic function, are often affected first. 
Clinically detectable impairment of touch sensation and motor func­
tion frequently follows after several months. Unfortunately, tools that 
allow reliable and safe testing of pain and temperature sensation and 
autonomic function often are not available at peripheral health facili­
ties, but simple and reliable tests of touch sensation and motor function 
do provide a reflection of the underlying neuropathy.
TOUCH SENSATION TESTING  The ulnar and median nerves and the 
posterior tibial nerve are usually tested for touch sensation. The most 
reliable test is the Semmes-Weinstein monofilament (SWM) test. If 
the impairment is of <6 months’ duration and/or new nerve function 

impairment is diagnosed, glucocorticoid treatment should be given. 
Because filaments are not available in most peripheral health centers, 
the WHO recommends that a ballpoint pen be used instead. The test­
ing protocol is the same as in the SWM test: the stimulus is delivered 
by touching the test sites with the tip of a ballpoint pen held at an angle 
of ~45° relative to the skin.
VOLUNTARY MUSCLE TESTING  Motor function of the hands and feet 
should be evaluated by voluntary muscle testing. The muscle functions 
most affected in leprosy are eye closure (facial nerve), finger abduc­
tion (ulnar nerve), thumb opposition (median nerve), wrist exten­
sion (radial nerve), and ankle extension (common peroneal nerve). 
Strength is assessed with a WHO-recommended system as strong, 
weak, or paralyzed.
NERVE CONDUCTION TESTS  Testing of nerve conduction parameters 
is sensitive in detecting early signs of peripheral neuropathy in lep­
rosy. Sensory nerve conduction parameters are often affected several 
months ahead of clinical tests (e.g., the SWM test). However, a trial of 
glucocorticoid treatment of such early changes did not show improved 
long-term outcomes, perhaps suggesting that the glucocorticoids are 
unable to switch off or reverse the pathologic process.
ULTRASOUND TESTING OF NERVES  Palpable enlargement of certain 
peripheral nerves is one of the cardinal signs of leprosy. Definite 
enlargement is easy to establish, but milder degrees are much harder to 
diagnose by palpation. Ultrasound imaging and measurement of nerve 
diameters—even with portable equipment—can detect nerve enlarge­
ment accurately. This technique may be used to support the diagnosis 
of leprosy and may indicate the onset of neuropathy that warrants antiinflammatory treatment.
OTHER TESTS OF PERIPHERAL NERVE FUNCTION  Pain and tempera­
ture sensation are commonly affected in leprosy neuropathy. However, 
these sensations are difficult to test safely and reliably under field 
conditions. Studies have shown that heat detection thresholds are 
often affected several months before touch sensation is impaired. Laser 
Doppler measurement of autonomic vasomotor reflexes is a sensitive 
method for detection of peripheral autonomic nerve damage in leprosy 
patients.
TREATMENT
Leprosy, Leprosy Reactions, and Other Major 
Manifestations
TREATMENT OF LEPROSY
Multidrug Therapy  Only one multidrug regimen is recommended 
by the WHO for the treatment of leprosy. This regimen consists 
of a combination of two or three of the following drugs: rifampin, 
dapsone, and clofazimine (Table 184-1). The keystone of WHOrecommended multidrug therapy for multibacillary leprosy is a 
monthly dose of rifampin together with daily doses of dapsone and 
daily and monthly doses of clofazimine. Patients with paucibacil­
lary leprosy are treated with two drugs, receiving monthly doses of 
rifampin and daily doses of dapsone. The treatment duration is 
12 months for multibacillary disease and 6 months for paucibacil­
lary disease. Provided that patients complete therapy, treatment 
failure rates are very low.
Some studies have investigated a uniform regimen of three 
drugs for 6 months. In a recent systematic review of evidence on 
the potential benefits and risks of this shorter regimen, the WHO 
concluded that relevant evidence is limited and inconclusive, with a 
potential increase in the risk of relapse. Therefore, the WHO does 
not recommend a shortened treatment duration for multibacillary 
leprosy.
The WHO further recommends supervised intake, but actual 
practice varies among countries. Through the WHO, multidrug 
therapy is provided free of charge as blister packs for adults to 
all countries reporting leprosy. Blister packs are also provided for

TABLE 184-1  WHO-Recommended Multidrug Treatment for Leprosy
PAUCIBACILLARY 
LEPROSYa
MULTIBACILLARY 
LEPROSYb
DRUG, AGE GROUP
Dapsone
Adult
100 mg/d
100 mg/d
Child age 10–14 years
50 mg/d
50 mg/d
Child <10 years
Dose adjusted to body 
weight
Dose adjusted to body 
weight
Rifampin
Adult
600 mg monthly
600 mg monthly
Child 10–14 years
450 mg monthly
450 mg monthly
Child <10 years
Dose adjusted to body 
weight
Dose adjusted to body 
weight
Clofaziminec
Adult
—
50 mg/d plus 300 mg 
monthly
Child 10–14 years
—
50 mg/d plus 150 mg 
monthly
Child <10 years
—
Dose adjusted to body 
weight
aDuration: 6 doses (6 blister packs). bDuration: 12 doses (12 blister packs). cIn 
2018, the World Health Organization (WHO) suggested including clofazimine in the 
multidrug therapy regimen for paucibacillary leprosy as well, but it is questionable 
whether this suggestion will be implemented because of the possibility that skin 
discoloration might compromise compliance. In addition, this alteration would 
involve a major change in the production of blister packs, which currently do not 
include clofazimine for paucibacillary leprosy patients (in line with the original WHO 
recommendation).
10- to 14-year-olds, while younger children are given doses adjusted 
according to body weight (Table 184-1).
Adverse Events  •  Rifampin  Rifampin acts by inhibiting 
DNA-dependent RNA polymerase, thereby interfering with bacte­
rial RNA synthesis. Rifampin is well absorbed orally. Hepatotoxicity 
may occur with a mild transient elevation of hepatic aminotrans­
ferases, but this reaction is rare at the dosages and intervals recom­
mended for leprosy and is not an indication for discontinuation 
of treatment. Because rifampin is given only monthly in WHOrecommended multidrug therapy regimens, the adverse effects 
recognized from its use in tuberculosis probably do not occur. A 
monthly dose of rifampin does not cause induction of hepatic cyto­
chrome p450. Urine discoloration occurs but is harmless. 
Dapsone 
Dapsone (4,4-diaminodiphenyl sulfone [DDS]) acts by 
blocking folic acid synthesis and is only weakly bactericidal. Oral 
absorption is good, and the drug has a long half-life averaging 28 h. 
Dapsone has a poor safety profile, and its use should be monitored 
carefully. In the doses recommended for leprosy, it can cause mild 
hemolysis and may cause anemia or, rarely, psychosis. Glucose6-phosphate dehydrogenase deficiency seldom causes a problem, 
and enzyme levels are not routinely tested before the start of mul­
tidrug treatment. On the other hand, the “DDS syndrome” (also 
called the dapsone hypersensitivity syndrome) is a severe adverse 
event that is not uncommon in some countries. It usually devel­
ops 6 weeks after the commencement of dapsone administration 
and manifests as fever, skin rash, eosinophilia, lymphadenopathy, 
hepatitis, and encephalopathy. Other rare but severe cutaneous 
adverse reactions are erythema multiforme, Stevens-Johnson syn­
drome, toxic epidermal necrolysis, and exfoliative dermatitis. The 
fatality rate for DDS syndrome is 10%, with death occurring from 
liver failure, sepsis, and bone marrow failure. Most patients require 
treatment with systemic glucocorticoids. In all cases, dapsone treat­
ment must be stopped. Agranulocytosis, hepatitis, and cholestatic 
jaundice occur rarely with dapsone therapy. 
Clofazimine 
Clofazimine is a brick-red, fat-soluble crystalline 
dye. The mechanism of its weakly bactericidal action against M. leprae 
is not known. High drug concentrations are found in the intestinal 

mucosa, mesenteric lymph nodes, and body fat. The most notice­
able adverse event is skin discoloration ranging from red to purple 
or black, with the degree of discoloration depending on the dosage. 
Clofazimine can accumulate in active leprosy skin lesions, thus 
making them more prominent. The abnormal pigmentation usually 
fades within 6–12 months of clofazimine discontinuation, although 
traces of discoloration may remain for up to 4 years. The skin dis­
coloration associated with clofazimine is psychologically distressing 
for many people. Patients often stop taking the drug because the 
discoloration is socially disabling for them, alerting their social 
environment to the fact that they are taking anti-leprosy medication 
and thus breaking confidentiality about treatment. Urine, sputum, 
and sweat may become pink during clofazimine administration. 
Clofazimine also produces a characteristic ichthyosis on the shins 
and forearms. Adverse gastrointestinal events ranging from mild 
cramps to diarrhea and weight loss may result from clofazimine 
crystal deposition in the wall of the small bowel.

Relapse  The cure rate for leprosy with multidrug therapy is 99%, 
but relapse is possible. In multibacillary leprosy, relapse is defined 
as the multiplication of M. leprae, with an increase of at least 2+ 
over the previous value in the bacteriologic index at any single site; 
this change usually occurs in conjunction with evidence of clinical 
deterioration (e.g., new skin patches or nodules and/or new nerve 
damage). Relapse rates are well below 1% except among a small pro­
portion of patients who have a very high bacillary load at the start 
of treatment (bacteriologic index ≥4). In different studies, four to 
seven relapses were recorded per 100 person-years. These relapses 
usually occurred <5 years after the end of multidrug therapy. Since 
antimicrobial resistance to the combination of drugs used in multi­
drug treatment is rare, patients with relapse can be re-treated with 
the same multibacillary regimen.
CHAPTER 184
Recognizing a relapse in paucibacillary leprosy can be difficult, 
as symptoms may resemble T1R. However, relapse of paucibacil­
lary disease is very rare. Administration of a therapeutic trial with 
glucocorticoids to patients with new lesions may help distinguish 
between these two phenomena: a definite improvement within 4 weeks 
of initiation of glucocorticoid therapy indicates T1R, whereas a lack 
of response favors the diagnosis of a clinical relapse. Patients with 
multibacillary disease who present with a relapse are re-treated with 
the multidrug regimen regardless of any change in classification. 
Patients with paucibacillary disease require 2 years of monitoring 
after treatment and patients with multibacillary disease at least 5 years. 
Reinfection by different strains of M. leprae is possible and can be 
confused with relapse.
Leprosy
Rifampin Resistance and Second-Line Drugs  Resistance to 
rifampin has been reported from several countries, although the 
number of patients involved is small. Evidence on the potential 
benefits and risks of using alternative regimens for drug-resistant 
leprosy is not available. Therefore, recommendations provided by 
the WHO for second-line regimens are based on expert opinion 
and the known activity of alternative drugs, including the likeli­
hood of cross-resistance. For rifampin-resistant leprosy, the WHO 
guidelines recommend daily treatment with at least two second-line 
drugs—clarithromycin, minocycline, or a quinolone (ofloxacin, 
levofloxacin, or moxifloxacin)—plus clofazimine for 6 months, 
followed by clofazimine plus one of the second-line drugs daily for 
an additional 18 months. Leprosy patients infected with M. leprae 
resistant to both rifampin and ofloxacin may be treated daily with 
the following regimen: clarithromycin, minocycline, and clofazi­
mine for 6 months, followed by clarithromycin or minocycline plus 
clofazimine for an additional 18 months.
TREATMENT OF LEPROSY REACTIONS
Type 1 Reactions  Oral, short-acting glucocorticoids are the treat­
ment of choice for T1R. Prednisolone is used most often in an initial 
dose of 1 mg/kg of body weight once a day, usually with a maximum 
of 60–80 mg. If standard treatment protocols are followed, as they 
are in most leprosy programs in endemic countries, an initial dose

PART 5
Infectious Diseases
of 40 mg of prednisolone is recommended by the WHO. The dose 
is tapered slowly, usually by 5 mg every 2 weeks over a period of 
20 weeks—a schedule that results in better outcomes and lower 
reaction relapse rates than the previously recommended 12-week 
glucocorticoid regimen. However, the clinical response should 
guide treatment. Patients should be examined every 2 weeks, and 
the examination should include a quick nerve function assessment. 
Not infrequently, the reaction flares up again once the daily gluco­
corticoid dose is tapered to <10–20 mg. The potential benefits of 
longer treatment should be balanced against the risks of prolonged 
glucocorticoid use, especially at higher doses.
Type 2 Reactions  Mild first-time T2R (or ENL) reactions with 
localized skin nodules may be treated with aspirin and pentoxifyl­
line. If a rapid effect is needed, the most effective drug to date is tha­
lidomide, which rapidly suppresses clinical signs, including nerve 
impairment and iritis. However, the drug is blacklisted in many 
countries because of its teratogenicity. If available, it should be given 
with great caution to women of childbearing age—only after careful 
counseling and a negative pregnancy test and with strict adherence 
to contraception. A dose of 100–200 mg is given either once or 
twice daily. In acute first episodes, thalidomide treatment should 
be tapered down and stopped after 1–2 weeks. If tissues other than 
the skin are affected—e.g., the eyes (iritis/uveitis), testes (orchitis), 
kidneys (nephritis), or joints (arthritis)—longer treatment may be 
needed until signs and symptoms have resolved. In patients with 
severe recurrent ENL, a daily thalidomide maintenance dose of 
50 mg may be effective in suppressing new episodes. Because of 
the restricted availability and use of thalidomide, patients with 
acute ENL are usually treated with glucocorticoids. T2R tends to 
be transient, often resolving in ~2 weeks. The treatment strategy is 
therefore to suppress the acute signs and symptoms with high-dose 
oral prednisolone, quickly tapering treatment in 2–3 weeks either 
to zero or to a low maintenance dose if the patient has had previous 
attacks. High-dose clofazimine also is effective in preventing recur­
rent ENL, but attainment of a maximal effect takes several weeks. 
The usual regimen is 300 mg daily for 1 month, followed by 200 mg 
daily for 1 month and, subsequently, 100 mg daily as a mainte­
nance dose for as long as necessary. Prolonged use of high-dose 
clofazimine may cause significant adverse gastrointestinal effects. 
An important side effect of clofazimine is a dark discoloration of 
the skin. While discoloration resolves gradually after the drug is 
discontinued, it is one main reason that patients dislike or even 
refuse to take clofazimine.
TREATMENT AND PROGNOSIS OF NERVE 
FUNCTION IMPAIRMENT
Episodes of sensory or motor nerve function impairment without 
skin signs are common. Neuropathy may occur without obvious 
neuritis. Still, the treatment of such “silent neuropathy” is the same 
as that for T1R. High-dose prednisolone is the drug of choice. Some 
experts think that patients will benefit from nerve decompression 
surgery, but evidence from randomized controlled trials is lacking.
If glucocorticoid treatment is started shortly after the develop­
ment of nerve function impairment, the prognosis for full recov­
ery is good. Generally, some recovery can still be expected up to 
6 months after onset, but the likelihood of recovery diminishes 
with every new episode. Generally, nerve function impairment that 
has persisted for >6 months does not benefit from glucocorticoid 
treatment.
TREATMENT OF (NEUROPATHIC) PAIN
Pain is common in people affected by leprosy and is often of neuro­
pathic origin. Little evidence-based information is currently avail­
able on the origin and treatment of pain in leprosy. Generally, for 
the treatment of neuropathic pain, three classes of medication are 
available: tricyclic antidepressants, phenothiazines, and anticonvul­
sants (carbamazepine, oxcarbazepine, gabapentin, and pregabalin). 
These agents can be combined with analgesics and anti-inflamma­
tory drugs according to the patient’s needs.
DISEASE MANAGEMENT DURING TREATMENT
Leprosy can be cured effectively, but the long duration of multidrug 
therapy means that careful management is needed to help the patient 
complete treatment. Regular visits to a health center may invoke 
questions from community members that may threaten the patient’s 
privacy, thus causing the patient mental distress and jeopardizing 
treatment adherence. Counseling is essential, as are patient-friendly 
arrangements for collecting treatment drugs. The disease, its treat­
ment, and its possible complications should be discussed, including 
a consideration of disease prognosis, the resolution of skin patches, 
skin discoloration by clofazimine, the lack of contagiousness during 
multidrug therapy, and the capacity for unrestricted family relations, 
including marital life and sexual activity. Possible stigmatization, 
including self-stigmatization, also should be discussed.
Because of the diverse complications that are possible, especially 
in patients with multibacillary leprosy, a multidisciplinary approach 
to patient management is required. In low-income countries, the 
responsibility for treatment usually lies with a leprosy control offi­
cer or a general medical practitioner. In middle- and high-income 
countries, the main treatment responsibility usually falls to a der­
matologist. Additional support should come from a neurologist or 
neurophysiologist for the diagnosis of nerve function impairment, 
and a rehabilitation physician, physiotherapist, infectious disease 
specialist, and/or psychologist may be needed. Occasionally, spe­
cialist support with regard to orthotics as well as in ophthalmology, 
occupational therapy, reconstructive surgery, and/or communitybased rehabilitation is indicated.
Supervised Multidrug Therapy  Regular treatment is important, 
especially the supervised 4-weekly dose of rifampin and clofazi­
mine. However, treatment adherence can be facilitated by flexible 
arrangements; for example, patients can be allowed to take home 
more than one 4-week blister pack if they will be away for travel or 
seasonal labor. In such cases, a family member or another respon­
sible person can be asked to supervise the monthly dose.
Monthly Nerve Function Assessment  Since nerve damage can be 
insidious and silent, it is important to conduct a brief nerve function 
assessment at each clinic visit during multidrug therapy. This regular 
assessment is especially important in patients with known risk fac­
tors for nerve function impairment. At highest risk are patients with 
multibacillary disease, who already have nerve damage at the start of 
treatment. Their risk of additional nerve damage is as high as 65%. 
Multibacillary leprosy patients without nerve function impairment 
at diagnosis and paucibacillary leprosy patients with such impair­
ment at diagnosis have a 16% chance of developing damage and 
additional damage, respectively. Patients with paucibacillary disease 
who do not have nerve function impairment at diagnosis are at low­
est risk (3%); for them, an assessment at the start and completion 
of multidrug therapy can be sufficient. Leprosy reactions and new 
nerve damage may also occur after completion of multidrug treat­
ment. While the risk diminishes with time, these manifestations can 
occur up to 3 years after the conclusion of therapy.
Health Education  During treatment, patients will have questions 
that need to be addressed in order to ensure their treatment adher­
ence. Sensitive questions may arise regarding everyday life within 
the family and at work that, if not addressed properly, could lead 
to social withdrawal and mental health issues. Crucial points for 
health education are at diagnosis and at completion of treatment. 
When communicating the diagnosis, the physician must explain 
that the disease is caused by a curable microbial infection and must 
cover the possible discomforts of drug intake, the interruption 
of disease transmission through drug intake, and the importance 
of adhering to treatment to achieve a cure. At the completion of 
multidrug therapy, the emphasis should be on separating the con­
cept of cure (bacterial activity) from the sequelae of the disease 
(nerve function impairment, leprosy reactions, and disabilities) 
and explaining that the patient may need to continue receiving 
health care, including reconstructive surgery, for the sequelae. 
Patients often associate cure with the absence of symptoms, which

is not accurate in leprosy. Some patients will experience discomfort 
during bacterial activity but will have no sequelae after treatment. 
In others, nerve function impairment or leprosy reactions may 
cause disfigurement with physical discomfort after cure. These 
sequelae will need further management and patients at risk should 
be warned that such posttreatment complications may occur and to 
report without delay should this happen. Disabilities such as claw 
hand or neuropathic foot require chronic care.
Guidelines After the Completion of Multidrug Therapy  Patients 
should receive counseling at release from treatment. The topics 
covered should include reassurance that the person is no longer 
contagious, that in some patients hypopigmentation in skin lesions 
may not resolve for a long time, and that skin discoloration due to 
clofazimine will gradually disappear in the following months. Nerve 
impairment may continue to improve after release from treatment, 
but this is by no means certain. Most important, patients should be 
instructed to return to the clinic if any new skin signs or fresh nerve 
damage occurs. This situation is not uncommon, is usually due to 
a leprosy reaction, and should be managed carefully from both a 
medical and a social perspective, since patients and persons in their 
environment will interpret this development as “leprosy coming 
back.” Patients at risk of further episodes of reaction and/or addi­
tional nerve function impairment (e.g., patients with preexisting 
nerve function impairment and multibacillary infection or patients 
who have experienced a reactional episode during therapy) should 
be asked to return for a check-up every 6 months for at least 3 years 
after being released from treatment.
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■REHABILITATION AND SOCIAL ASPECTS
Physical Rehabilitation 
Peripheral neuropathy and its second­
ary disabling consequences often require physical rehabilitation. This 
effort may include reconstructive surgery in the case of facial, ulnar, 
median, or posterior tibial paralysis. In this case, pre- and postopera­
tive physical therapy is of crucial importance. Physical therapy is also 
indicated when muscles are not completely paralyzed or when con­
tractures are too stiff to allow surgery. Since paralysis is usually accom­
panied by sensory and autonomic neuropathy, occupational therapy 
also is helpful; therapists teach patients how to minimize the risk of 
further injury and other techniques for prevention of disabilities. The 
key principle is teaching patients and former patients to self-manage 
their disabilities. In many programs, this teaching occurs in the setting 
of self-care groups. A well-tested and evidence-based self-care routine 
for hands and feet consists of inspection, soaking, scraping, and oiling 
(ISSO). Specifically, in ISSO, the person inspects the affected limbs 
for hotspots (evidence of too much stress on an area of skin): wounds, 
cracks, and calluses. Next, the affected limb(s) are soaked in plain water 
for 15 minutes. While the skin is wet, areas with excess calluses are 
scraped with a rough stone or another rough object. The skin is then 
rubbed with petroleum jelly or another nonfragrant oil in order to trap 
moisture in the skin. If this routine is performed daily, the skin can 
be kept supple and in good condition, despite sensory and autonomic 
damage. If sensation on the soles of the feet is impaired, the person 
must wear protective footwear. Simple footwear (e.g., sandals or sneak­
ers) available at the local market is adequate as long as it has a strong 
sole and a soft insole of ethylene-vinyl acetate or microcellular rubber 
that distributes pressure—an especially important feature when foot 
muscles are weak or paralyzed or the architecture of the foot is dam­
aged, as is often the case with neuropathy. In high-resource settings, 
tailor-made orthopedic shoes can be provided.
Mental and Social Support 
Like other chronic health conditions, 
leprosy requires patients to cope with the burden of new routines in 
everyday life. In addition to coping with stigma, they must organize 
themselves for prolonged treatment, prevention of disabilities, and 
rehabilitation activities. Moreover, like other neglected tropical dis­
eases (see “Neglected Tropical Diseases,” below), leprosy may lead to 
poor mental health. Such diseases are accompanied by social exclusion 
in the form of poor access to services such as health care, education, 

employment, and housing. This exclusion accounts for common 
mental health comorbidities in leprosy patients and their family mem­
bers, including depression, anxiety, and suicidal thoughts. Leprosy is 
probably the most notorious of all stigmatized health conditions, and 
social stigmatization is the most common issue that triggers mental 
suffering. Other infectious diseases that raise this issue include HIV 
infection, tuberculosis, and neglected tropical diseases like lymphatic 
filariasis, Buruli ulcer, and dermal leishmaniasis. Although the rea­
sons for stigmatization vary, the manifestations and interventions that 
effectively reduce stigma are similar across conditions and countries. 
Therefore, joint interventions addressing health-related stigmas for 
multiple conditions would be strategically and financially attractive. 
The need to introduce mental health care in leprosy services is press­
ing. Therapeutic group meetings among institutionalized patients and 
self-care groups at the community level, with a focus on prevention of 
disabilities and mental well-being, are known to ameliorate depression, 
encourage self-acceptance, and promote confidence.

NEGLECTED TROPICAL DISEASES  Leprosy is one of a medically 
diverse group of 20 neglected tropical diseases (NTDs). This group 
includes infectious diseases caused by bacteria, viruses, fungi, and 
parasites as well as some noninfectious conditions, such as podoco­
niosis and snakebite. NTDs have been grouped together because they 
affect 1.5 billion of the poorest people on Earth and have been widely 
neglected in domains such as public policy, funding, and the develop­
ment of diagnostics and treatments. Leprosy is the archetypical NTD, 
featuring all of the common characteristics: a treatable infectious dis­
ease, a known population at risk, available preventive chemotherapy, 
disease complications that may lead to severe disabilities, and a per­
vasive social stigma that leads to discrimination, social exclusion, and 
severe mental health consequences. Nevertheless, the priority accorded 
to leprosy on the public health agenda of most endemic countries is 
very low. By joining hands in advocacy, fundraising, and development 
of joint control strategies, health care organizations can substantially 
raise the priority profile of NTDs, benefiting each of the individual 
disease control programs. Such a joint approach serves the goal of 
universal health coverage and helps to strengthen health services more 
effectively than vertical programs are ever able to do on their own.
CHAPTER 184
Leprosy
■
■PREVENTION AND CONTROL
Interruption of Transmission and Novel Preventive 

Strategies 
Leprosy control was traditionally based on early case 
detection and multidrug treatment. Apart from health education and 
leprosy awareness campaigns, no preventive measures were available. 
In the 1990s, authorities hoped that the transmission of M. leprae in the 
community could be interrupted through timely detection of cases and 
provision of multidrug therapy, leading to a decline in leprosy incidence. 
Unfortunately, this has not been the case (Fig. 184-1). The inability to 
reduce leprosy incidence in many countries and the heightened interest 
in NTDs have invigorated research into new techniques for the diagno­
sis of disease and infection, leprosy vaccines, enhanced postexposure 
chemoprophylaxis regimens, epidemiologic tools (e.g., geographic infor­
mation systems for identifying leprosy hotspots), surveillance of antimi­
crobial resistance, and alternative drugs and drug treatment regimens.
Vaccines Against Leprosy 
The bacille Calmette-Guérin (BCG) 
vaccine used against tuberculosis provides varying degrees of protec­
tion against leprosy and is used routinely as postexposure immuno­
prophylaxis for contacts of leprosy patients in Brazil. Two promising 
vaccine candidates are in the pipeline: the MIP vaccine from India, 
which is based on killed Mycobacterium indicus pranii, and the syn­
thetic LepVax vaccine developed by the University of Washington’s 
Infectious Disease Research Institute in the United States. If proven 
effective, these vaccines, like the BCG vaccine, will be used as postex­
posure prophylaxis for contacts of leprosy patients. Trials are in early 
stages, and sufficient proof of efficacy will take years.
Postexposure Chemoprophylaxis 
The introduction of post­
exposure chemoprophylaxis (PEP) for household and other close 
contacts of leprosy patients is an important innovation. A large