CHAPTER
41
Leprosy
WINNIE W. OOI’JAYASHRI SRINIVASAN
INTRODUCTION
EPIDEMIOLOGY
HOST FACTORS
BACTERIAL FACTORS
CLINICAL MANIFESTATIONS
Lepromatous Leprosy
Tuberculoid Leprosy
Borderline Leprosy
Primary Neuritic Leprosy
Autonomic Neuropathy in Leprosy
Pain in Leprosy
DIAGNOSTIC STUDIES
Electrodiagnostic Studies
INTRODUCTION
Leprosy is one of the oldest diseases known to afflict
humans, with descriptions of the disease present in
sixth century BCE Indian texts. It is caused by Mycobacte-
rium leprae (M. leprae), the organism first identified by
the Norwegian physician, Gerhard Hansen, in 1873. It
is an obligate intracellular acid-fast bacillus, which is
detected in tissues by the modified Fite-Faraco stain
(Fig. 41-1). In 2008 a new species, M. lepromatosis, was
identified in Mexico and is now known to cause a syn-
drome that is clinically equivalent in all respects to clas-
sic leprosy. Neither species grows in culture, and with
the exception of armadillos, certain primates such
as the chimpanzee and macaque, and red squirrels,
humans are the primary reservoir and source of infec-
tion. The genome of the organism was sequenced in
2001 and has undergone reductive evolution, with
only 49.5 percent of its genes being involved in cod-
ing.1 The route of transmission is primarily through
nasal droplets. Skin-to-skin contact is not thought to
be an important route of infection. Other modes of
Aminoff’s Neurology and General Medicine, Sixth Edition.
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Ultrasonography
Nerve Biopsy and Pathology
MYCOBACTERIAL TREATMENT
Side Effects of Multidrug Treatment
Drug Resistance and Treatment of Relapses
LEPROSY REACTIONS
Type 1 Lepra Reactions (Reversal Reactions)
Type 2 Reactions
LEPROSY AND HUMAN IMMUNODEFICIENCY VIRUS
INFECTION
PREVENTION
CONCLUDING COMMENTS
transmission have been documented and are rare; they
include contact with infected soil and direct dermal
implantation such as occurs during tattooing. In sus-
ceptible individuals, the organisms rapidly gain access
to cooler dermal tissues, primarily to cutaneous and
subcutaneous nerves, and neural networks, skin appen-
dages, sweat glands, and erector pili muscles. Scollard
and colleagues demonstrated that endoneurial vessels
in the armadillo serve as the route of entry into the
nerve, by demonstrating extensive infection of endo-
thelial cells of endoneurial, epineurial, and perineurial
blood vessels.2
Leprosy is the leading cause of infectious neu-
ropathy in the developing world. The considerable
social stigma that has been associated with this diag-
nosis through the ages has persisted and can pre-
vent early detection and effective treatment. Not
only does M. leprae have a predilection for Schwann
cells, but the immunologically mediated reactions
seen during antimicrobial therapy cause significant
damage to the peripheral nervous system and con-
tribute substantially to disability.
728 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE

EPIDEMIOLOGY
The prevalence of leprosy, defined by the World Health
Organization (WHO) as those who are on active myco-
bacterial treatment, has declined by 96 percent over
the last 20 years. This is largely due to the worldwide
implementation since 1982 of progressively shorter
courses of multidrug therapy (MDT). By 1982, the inci-
dence of leprosy had already declined significantly in
countries such as China and Mexico, coinciding with
improvement in nutrition and living conditions, and
with widespread bacille Calmette-Guérin (BCG) vacci-
nation, which is variably protective against leprosy.
Since the year 2000, however, some 200,000 new cases
of leprosy have been detected every year. Although
these new cases include individuals who acquired their
infection years earlier, there is evidence that transmis- FIGURE 41-1 ’ Fite-Faraco stain reveals acid-fast bacilli in
sion of leprosy is continuing unabated, with delays in the nerve, seen in skin biopsy at 100 3 magnification.
diagnosis and treatment. At least 9 percent of new cases
over the past decade have been in children, and high
tuberculoid (BT), borderline (BB), borderline lepro-
rates of disability have been seen in new cases in several
matous (BL), and lepromatous leprosy (LL) forms
countries. The latest WHO target for 2020 includes
(Table 41-1). Patients with tuberculoid leprosy have
decreasing the number of new patients diagnosed with
an excellent cell-mediated immune (Th1) response
deformities to less than one per million, and the num-
to M. leprae. This manifests as few skin lesions, which
ber of children with disabilities to zero. The decreased
histologically have well-organized granulomas (in which
incidence numbers do not take into account patients
bacteria are rarely found) with CD4-predominant
who have significant residual disabilities that require
T cells. Patients who have less effective cell-mediated
ongoing treatment or rehabilitation after completion
immunity have more aggressive clinical and bacterio-
of MDT. Furthermore, clinicians taking care of patients
logic expression of the disease, known as border-
with leprosy will continue to treat relapses and reactions
line disease. Finally, patients with LL are anergic to
for years after completion of MDT.
M. leprae, with predominant T-helper 2 (Th2) response,
resulting in uncontrolled growth of bacilli and dis-
HOST FACTORS seminated skin lesions. The reduced cell-mediated
immunity to M. leprae in LL is specific for this organ-
The clinical spectrum of leprosy correlates with the cell- ism and does not represent a generalized immune
mediated immunity of the patient. This is the basis for deficiency against other pathogens. Interferon-gamma
the Ridley-Jopling classification, which includes inde- (IFN-γ) production by T cells is another key component
terminate leprosy (I), tuberculoid (TT), borderline of the protective response against mycobacteria, as this

TABLE 41-1 ’ Spectrum of Leprosy

Classification Leprosy Spectrum
Ridley and Tuberculoid Borderline Borderline Borderline Lepromatous
Jopling Tuberculoid Lepromatous
WHO Paucibacillary Multibacillary
Up to five skin lesions Six or more skin lesions (or any nerve
involvement with few lesions)
Slit skin smears negative Slit skin smears positive
Higher ← Cell Mediated Immunity → Lower

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cytokine stimulates infected macrophages to kill intra-
cellular M. leprae. In TT leprosy there is increased
expression of type-1 cytokines IFN-γ and tissue necro-
sis factor-alpha (TNF-α), whereas in LL disease there
is a predominance of the type-2 cytokines such as
interleukin-10 (IL-10). Histologic examination of LL
lesions reveals sheets of foamy macrophages in the der-
mis, containing large numbers of bacilli in microcolo-
nies packed in parallel, like cigarettes in a packet, called
“globi” with small numbers of CD81 T cells. In the
WHO’s simplified clinical classification scheme, TT
and BT types are identified as “paucibacillary” (PB, 2
to 5 skin lesions) and types BB LL as “multibacillary”
(MB) (Table 41-1).
Genetic susceptibility to leprosy has been postulated
as an important factor in the acquisition and manifesta-
tion of leprosy.3 HLA genes may also influence the
type of leprosy that develops; for example, tuberculoid
leprosy develops more frequently in individuals with
HLA-DR3, whereas LL is more prone to develop in
those with HLA-DQ1 or HLA-MT1. Toll-like receptor
(TLR) activation plays an important role in innate
immunity to pathogens by the upregulation of antigen-
presenting molecules and secretion of cytokines. Toll-
like receptor 1 and 2 (TLR1 and TLR2) expression in
monocytes has been found to correlate with the clinical
presentation of leprosy, especially TLR2 microsatellite
polymorphisms and TLR2 SNP. Patients with tubercu-
loid leprosy strongly express these receptors, whereas
patients with LL express them weakly.
BACTERIAL FACTORS
M. leprae’s affinity to Schwann cells is mediated by
Fc receptors, complement receptors, the fibronectin
binding protein, and TLR2.4 Phenolic glycolipid 1
(PGL-1), which is an M. leprae-specific antigen, has
been shown to bind to laminin of Schwann cells. PGL-1
also binds to complement (C3), and this complement
M. leprae complex in turn binds to macrophages and
monocytes via complement receptors (CR1, CR3,
and CR5), resulting in a three-component receptor
ligand acceptor molecule for mediating phagocytosis
of the organism by human monocytes. M. leprae
attaches to Schwann cells via PGL-1, binding specifi-
cally to the G domain of the α-2 chain of laminin-2
(a protein constituent of the extracellular basal lam-
ina) that, in turn, binds to α-dystroglycan on the plasma
membrane of the Schwann cells.
In a classic series of experiments, Rambukkana and
colleagues showed that M. leprae preferentially invades
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LEPROSY 729
nonmyelin-producing Schwann cells where the organ-
isms multiply in large numbers, serving as a reservoir
for organism growth.4 After attachment of the organ-
ism, myelin-producing Schwann cells undergo signifi-
cant loss of myelination by an immune-independent
mechanism. Dystroglycan complexes link the basal
lamina to the cytoskeleton of Schwann cells through
membrane-associated linker proteins called dystro-
phins or utrophins, which are believed to transduce sig-
nals from the exterior to the interior of the cells.
Myelin-producing Schwann cells contain a third com-
plex, dystrophin-related protein 2 (DRP2), the disrup-
tion of which results in demyelination of nerves. It is
hypothesized that the loss of myelin production by
infected Schwann cells in leprosy may be due to the
interaction of PGL-1 with the DRP2 dystroglycan
complex. This is followed by dedifferentiation of the
Schwann cells to the nonmyelin-producing phenotype
that is very vulnerable to invasion by the bacteria.
The survival of M. leprae within Schwann cells is
greater at 33°C and therefore it has an affinity for
nerves at superficial, cooler sites. The Schwann cells
are also altered by infection, producing metabolic
and functional changes that trigger the immune
system in recruiting cytotoxic cells, T lymphocytes,
and macrophages. The end result is unrestrained
multiplication of the organism within Schwann cells,
destruction of myelin, inflammatory changes, and
secondary destruction of the nerve architecture. The
discovery that demyelination can be induced in vivo
by the bacterial cell-wall antigen alone may explain the
ongoing neurologic damage that can occur in leprosy
after treatment.
Nerve growth factor (NGF) is a neurotrophin pro-
duced by multiple cell types, including neurons, Schwann
cells, lymphocytes, and mast cells. The role of NGF
in leprosy is not fully understood but it is likely that it
is involved in the nerve damage and ensuing neuro-
pathic pain.5 Studies have shown that higher levels of
NGF are associated with LL and low levels are associ-
ated with tuberculoid forms of the disease. NGF may
also play a role in neuropathic pain, and this may be
an important pathway in developing future remedies
for pain.
The genome of M. leprae is the smallest among myco-
bacteria, with approximately 1,605 genes encoding
proteins and 1,300 pseudogenes. Compared to the bac-
terium causing tuberculosis, M. leprae reveals extreme
reductive evolution with less than half of the genome
containing functional genes. Reductive evolution,
gene decay, and genome downsizing may explain the
730 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE
TABLE 41-2 ’ Clinical and Histologic Aspects of Leprosy
Tuberculoid Leprosy (TT)
Dermatologic features Single or few anesthetic macules
or plaques with well-defined
borders.
Clinical features of Asymmetric nerve enlargement
neuropathy usually found proximal to skin
lesion.
Histopathology Destruction of nerve architecture
with granulomas in nerves.
Bacilli rarely seen.
unusually long generation time and the inability to
culture the organism in vitro. The genome is also
highly conserved, with ,300 single-nucleotide poly-
morphisms (SNPs) observed between distantly related
strains, and only a few SNPs between closely related
strains. Only 16 SNP subtypes have been defined.
Genotyping M. leprae strains from around the world
has enabled detailed phylogenetic and phylogeo-
graphic comparisons to be made, new mutations asso-
ciated with antimicrobial resistance to be detected,
and the likely origin of leprosy to be proposed. It has
allowed the identification of the new species, M. lepro-
matosis, and the study of the presence of zoonotic lep-
rosy in armadillos in the southern United States.
CLINICAL MANIFESTATIONS
The incubation period ranges from 3 months to 40
years, with an average of 7 years. The onset of the dis-
ease is insidious, with the skin and peripheral nervous
system primarily being involved.4 Three cardinal signs
remain the mainstay for the diagnosis of leprosy in clini-
cal practice: anesthetic skin lesions, enlarged peripheral
nerves, and acid-fast bacilli demonstrated by Fite-Faraco
staining in skin smears or skin biopsies (Fig. 41-1). The
bacilli favor the cooler areas of the body, such as the
chin, malar areas of the face, earlobes, buttocks, knees,
and distal extremities. Skin lesions range from the
asymptomatic, ill-defined, slightly hypopigmented, mac-
ule of indeterminate leprosy to the diffuse infiltration
seen in LL that causes thickening of the skin of the face
and earlobes (leonine facies). Approximately 5 percent
of patients present with nerve involvement without skin
lesions; this is called primary neuritic leprosy (PNL),
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Borderline Leprosy Lepromatous Leprosy (LL)
Many anesthetic lesions with ill- Multiple, nonanesthetic symmetrically distributed
defined to indistinct borders. macules or papules progressing to diffuse
Satellite lesions around larger infiltration of skin.
lesions.
Multiple nerves may be involved. No neural lesions until late, when bilateral
Involvement is earlier and symmetric distal neuropathies occur.
more rapid than in LL.
Findings range from those seen in Greater preservation of nerve structure with sheets
TT to those in LL with variable of foamy cells in the perineum resembling onion
presence of bacilli. skins. Numerous bacilli are seen.
the diagnosis of which may require nerve biopsy and
polymerase chain reaction (PCR) assistance. The clini-
cal and histopathologic features of the main types of
leprosy are shown in Table 41-2.
Lepromatous Leprosy
The initial manifestations of leprosy are due to direct
infection of dermal nerves resulting in anesthetic
patches. The nerve damage extends from this early
lesion with involvement of a small superficial nerve
twig and skin anesthesia to infection of many nerves
and involvement of larger skin areas. Patients may sub-
sequently develop more widespread neuropathies with
greater sensory and motor deficits, sometimes pre-
ceded by pruritus, paresthesias, and rarely pain. In
untreated cases, this type of leprosy becomes wide-
spread and symmetric within superficial skin tissues
and peripheral nerves. Because the immune response
to the bacilli in LL is very indolent, neuropathy usually
evolves over many years. As in tuberculoid disease, neu-
ropathies involving larger, superficially located nerve
trunks in the face, arms, and legs may also occur.
Initially, there is loss of thermal sense followed by
sequential loss of nociceptive and pressure sensations.
The affinity of M. leprae for Schwann cells and their pre-
dilection for cooler parts of the body have made certain
segments of nerve trunks vulnerable. The nerves most
likely to be involved are the ulnar nerve at the elbow,
the median nerve immediately proximal to the carpal
tunnel, the radial nerve at the spiral groove, the pero-
neal nerve at the fibular head, the tibial nerve proximal
to the ankle, and the facial nerve at the region of the
zygomatic bone. Sensory nerves such as the superficial
peroneal, posterior auricular, sural (Figs. 41-2 and 41-3),

FIGURE 41-2 ’ Patient with tuberculoid leprosy and an
enlarged posterior auricular nerve.
and superficial radial nerves and the dorsal branch of
ulnar nerve may also be involved. Unperceived trauma
secondary to sensory loss further aggravates the nerve
damage.
Mycobacteria also invade the anterior chamber of
the eye, upper respiratory tract, lymph nodes, perios-
teum, and testes. Eyebrows and eyelashes may be lost
(madarosis), and anesthesia of affected areas is exten-
sive and accompanied by anhidrosis. Sensory loss is
largely due to destruction of intracutaneous nerve end-
ings and first appears in cool areas, but with initial spar-
ing of the soles of the feet and palms of the hands.
There is also involvement of superficial facial nerve
twigs, causing lagophthalmos and paralysis of some
FIGURE 41-3 ’ Enlarged sural nerve with tuberculoid
lesion.
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LEPROSY 731
segments of the orbicularis oris and frontalis muscles.
The sensory loss spares warmer areas including the
intergluteal fold, the perineum, and the areas of the
scalp covered by hair. Despite the appearance of an
extensive sensorimotor neuropathy with clawed toes,
foot drop, and clawed hands, preserved muscle stretch
reflexes are the rule. Nerves that are grossly enlarged
and infiltrated with abundant bacilli may still function
well but are more susceptible to recurrent trauma.
Tuberculoid Leprosy
Nerve damage in tuberculoid leprosy is usually asym-
metric and is often confined to the nerves underlying
or near a skin lesion. Dermal nerves are infiltrated by
granulomas composed of epithelioid cells and lympho-
cytes, with destruction of Schwann cells and secondary
axonal damage. Nerves may be palpably enlarged and
painful; calcification of nerves sometimes occurs in
long-standing disease. The picture is generally one of a
clearly visible skin lesion that is usually hypopigmented,
with an elevated border (Fig. 41-3) and with a corre-
sponding demarcated patch of sensory loss and absent
sweating. Local bacillary invasion of nerves (although
acid-fast bacilli are rarely seen on biopsy) and a robust
immune response are the two factors that result in
focal, limited, and asymmetric disease. Motor, sensory, or
mixed nerves near a solitary tuberculoid patch may be
affected. Subcutaneous sensory nerves near the tubercu-
loid patch are often enlarged. The tissue response within
nerves may be so intense that there is necrosis and forma-
tion of a “cold” abscess. Enlarged nerves may be palpated
or demonstrated on ultrasound.
Borderline Leprosy
Neuropathy in borderline leprosy can produce the
most deformity as multiple nerves may be involved.
Nerve damage occurs more rapidly than in LL and irre-
versible nerve destruction may occur. Borderline lep-
rosy is immunologically unstable and movement along
the spectrum may occur: either an upgrading response
to the tuberculoid or a downgrading to lepromatous
forms. When the clinical illness is toward the tubercu-
loid spectrum (BT), there may be a single lesion
with asymmetric nerve involvement, but as the dis-
ease moves towards the lepromatous pole (BL) multi-
ple symmetric skin and nerve lesions may be seen
(Fig. 41-4).
732 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE
FIGURE 41-4 ’ Borderline lepromatous lesion.
Primary Neuritic Leprosy
This form is characterized by the presence of a neu-
rologic deficit and nerve thickening (with or without
tenderness) in the absence of clinical involvement of
the skin or mucosa. This presentation is seen in 5 to
20 percent of patients at leprosy treatment centers in
India. The clinical diagnosis of PNL may be difficult,
as these patients do not have characteristic anesthetic
skin lesions. However, blind biopsies of the skin near
enlarged nerves often show the histologic changes of
leprosy. Most of these patients present with a clinical pic-
ture consistent with mononeuritis multiplex, although
in one-third a single nerve is affected. Nerve trunks may
be significantly thickened and nodular. Ulnar and com-
mon peroneal nerves are commonly involved, although
any nerve may be affected. Electrophysiologic studies
reveal sensory and motor dysfunction of affected nerves,
usually with demyelinating features early in the dis-
ease, and axonal injury in later stages. Nasal mucosal
smears may show abnormalities including inflammation,
epitheloid granulomas, and bacilli in half of the patients.
Skin and nerve biopsies may show changes of leprosy
(ranging from BT to LL), with bacilli in about 50 per-
cent of patients. If nasal and skin pathology are nondiag-
nostic, nerve biopsies should be undertaken in patients
suspected of having PNL. A positive PCR increases the
sensitivity of detection of M. leprae in cases of probable
PNL when Fite stain is negative.
Autonomic Neuropathy in Leprosy
Autonomic dysfunction occurs early in leprosy, especially
in multibacillary disease, but it is often overlooked.
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Involvement of the small, unmyelinated, autonomic nerve
fibers results in hypohidrosis and alopecia of the anes-
thetic, hypopigmented skin patches. Reduced sweating
can often lead to dry, cracked skin that is prone to injury
and infection. With more extensive skin involvement,
there may be widespread impairment of sweating, result-
ing in heat intolerance. Impaired capillary blood flow
due to involvement of autonomic fibers in blood vessels
can result in stasis and impaired wound healing. Systemic
symptoms from autonomic dysfunction may also be seen,
including erectile dysfunction, heat intolerance, cardiac
arrhythmias, and ankle edema. Testing will show vasomo-
tor reflex impairment as measured by Doppler velocime-
try, and absent sympathetic skin responses. Involvement
of the parasympathetic system can be demonstrated by
reduced heart rate variability on deep breathing and
by the Valsalva maneuver. Autonomic dysfunction may
impair the quality of life even after treatment, as patients
may have persistent symptoms such as impaired sweating,
heat intolerance, and severe xerosis.
Pain in Leprosy
Neuropathic pain is frequent in leprosy and may occur
at all stages of the disease. Pain persists even after the
patient has been fully treated. Studies have shown that
the majority of patients have pain that is moderate to
severe in intensity; this has a significant negative effect on
their quality of life. Patients should be asked about their
pain and treated for this with analgesic medications.
DIAGNOSTIC STUDIES
Electrodiagnostic Studies
Electrodiagnostic studies have contributed signifi-
cantly to understanding the pathogenesis of the dis-
ease.4 They also help in establishing a baseline against
which response to treatment can be measured. Leprosy
initially causes segmental demyelination of peripheral
nerves with secondary axon loss. Early electrodiagnostic
findings in the disease therefore include prolongation
of distal latencies and segmental slowing of conduction
velocities, particularly when measured across vulnera-
ble sections of the nerves. If there is significant weakness
on clinical examination, there may be evidence of
conduction block or changes consistent with axonal
loss, that is, a reduction in amplitude of compound
muscle action potentials. Ulnar motor conduction stud-
ies reveal significant slowing of conduction across the

elbow segment, with relative sparing of the forearm,
wrist, and humeral segments. This selective involve-
ment of the elbow segment reflects the predilection of
the pathogen for cooler regions of the body. Median
motor studies reveal slowing in the distal third of the
forearm, usually proximal to the carpal tunnel. In the
lower extremities, peroneal studies are usually abnor-
mal, with slowing in conduction velocity in the segment
between the popliteal fossa and the fibular head, and
distally below the ankle, with prolongation of distal
latency. Facial motor studies may also be abnormal,
revealing prolonged latencies or reduced or absent
responses of the orbicularis oculi or frontalis muscles.
Even the phrenic nerve may be affected.
Needle electromyography may reveal reduced rec-
ruitment early in the disease, when there is weakness
due to focal demyelination. Later, increased insertional
activity and polyphasic, large-amplitude, long-duration
motor unit potentials with reduced recruitment may
be seen due to axonal loss and reinnervation. Late
responses such as the F response and H reflex are
often abnormal even without evidence of overt dis-
ease involving the nerves. Electrodiagnostic studies are
sometimes used to monitor response to therapy or
to monitor drug toxicity, particularly of thalidomide,
which is known to be associated with neuropathy.
Ultrasonography
High-resolution ultrasonography is increasingly useful
in leprosy.6 This is a relatively inexpensive diagnostic
method that is readily available, causes no discomfort,
and can be used to obtain information that is static
(size of the nerve, echo texture, nerve abscess) and
dynamic (Doppler studies of neural blood supply).
Studies have shown close correlation between abnor-
malities on ultrasound and nerve conduction studies
in leprosy. While electrodiagnostic abnormalities may
show evidence of nerve dysfunction, ultrasonography
shows evidence of nerve enlargement, abnormal echo
texture, and often increased epineural and endoneur-
al blood flow. Additionally it sometimes pinpoints the
site of maximum inflammation, which may help to deter-
mine the site of a nerve biopsy. In PNL, it may show
nerve involvement that is more extensive than occurs in
other mononeuropathies (such as entrapment neuropa-
thies), nerve abscesses that are rare complications of
PNL, and evidence of asymptomatic involvement of
other nerves. A unique sonographic pattern of nerve
enlargement is noted in patients with ulnar neuropathy;
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LEPROSY 733
the enlargement starts at the ulnar sulcus and is maximal
4 cm above the medial epicondyle. Asymmetric increase
of the cross-sectional area of the nerve at the same point
between right and left sides is an important feature of
leprosy. Finally, serial measurement of nerve thickness
and echo texture as well as vascularity measurements by
Doppler may help monitor response to treatment, and
changes in these measurements may be early harbingers
of relapse or the development of leprosy reactions.
Nerve Biopsy and Pathology
Nerve biopsies are rarely necessary in the right clinical
and epidemiologic setting as the diagnosis is usually
made clinically and confirmed by skin smears or skin
biopsies.2 However, nerve biopsies are sometimes neces-
sary to confirm a diagnosis of leprosy, especially in PNL,
or to exclude other causes of neuropathy. The nerve of
choice is a sensory cutaneous nerve that is enlarged,
such as the greater auricular (Fig. 41-2), superficial
radial, dorsal ulnar, or sural nerve (Fig. 41-3). The histo-
logic findings in nerve biopsies depend on the nature
and severity of the leprosy as well as on the presence or
absence of reactions.
In the tuberculoid (TT) and borderline (BT) sub-
types, light microscopy of nerve biopsies may reveal a
well-localized, intraneural granulomatous lesion involv-
ing a few nerve fascicles. Central caseous necrosis may
be present, surrounded by inflammatory cells consist-
ing of lymphocytes, epitheloid calls, and Langhans-
type giant cells sometimes surrounded by regenerating
myelin (Figs. 41-5 and 41-6). Bacilli are not seen com-
monly in TT or BT types and when present are usually
FIGURE 41-5 ’ Leprosy granuloma surrounded by
lymphocytes.
734 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE

PCR is very useful in diagnosing PNL when nerve biop-

sies have nonspecific changes and bacilli are not seen.
PCR was positive in about 62 percent of all patients with
PNL in an Indian study in which nerve biopsies were
obtained in patients with mononeuritis multiplex. The
positive and negative predictive values of PCR were 54.5
and 92.3 percent, respectively, in this population.7

MYCOBACTERIAL TREATMENT
In 1982, MDT was first recommended by the WHO to
replace dapsone monotherapy to prevent the emer-
gence of drug resistance.5 The key component of these
regimens was the bactericidal drug rifampicin. Since
1982 the recommended duration of treatment has
FIGURE 41-6 ’ Skin biopsy showing skin surface and non- decreased. The 2018 WHO guidelines (Table 41-3)
caseating granulomas (with one multinucleate giant cell). recommend a three-drug regimen of rifampicin,
dapsone, and clofazimine for all leprosy patients, to
found in Schwann cells. Granulomas extend from the be given for 6 months for PB leprosy and 12 months
perineurium to the endoneurium and sometimes also for MB leprosy.
involve the epineurium. Axon stains reveal significant Patients with any nerve involvement (including pri-
axonal loss that is sometimes confined to certain fasci- mary neural leprosy) are treated as MB disease. This
cles of the nerves. In late stages, significant fibrosis and represents a change from the prior treatment for
hyalinization of the endoneurium may occur and the
nerve architecture may be destroyed completely.
In the BL and LL subtypes, there is usually greater TABLE 41-3 ’ WHO Recommended Treatment Regimens
histologic preservation of nerve structure than in the Duration
tuberculoid type; axon stains may reveal some axonal
Dosage and MB PB
loss. Bacilli are numerous in Schwann cells and foamy Age Group Drug Frequency (months) (months)
macrophages (globi), and, to a lesser extent, in the
endothelial cells of endoneurial and perineurial vessels. Adult Rifampicin 600 mg once a month 12 6
Plasma cells are characteristic of the lepromatous sub-
Clofazimine 300 mg once a month
types; histiocytes are seen in the early stages of infection and 50 mg daily
while the presence of foamy macrophages indicates
Dapsone 100 mg daily
chronic infection. Epithelioid cells and nerve abscesses
are usually not seen in the BL and LL subtypes (except Children Rifampicin 450 mg once a month 12 6
(10 14
when there is a change in the grade to a BT/TT sub- Clofazimine 150 mg once a month,
years)
type). The perineurium may be split into layers by 50 mg on alternate
edema or sheets of foamy cells, giving the appearance of days

an onion-skin. However, as the disease progresses, more Dapsone 50 mg daily

significant destruction of the nerve architecture and Children Rifampicin 10 mg/kg once a month 12 6
matrix may occur; fibrosis may supervene with nerve ,10 years
Clofazimine 100 mg once a month,
destruction. Bacilli may be found in nerves for many or ,40 kg
50 mg twice weekly
years, even after treatment. Nerve biopsies may show
Dapsone 2 mg/kg daily
active disease with intact organisms in some patients
who are thought to have inactive disease clinically. Note: The treatment for children with body weight below 40 kg requires single
In borderline leprosy, nerve deformity may be signifi- formulation medications since no MDT combination blister packs are available. For
children between 20 and 40 kg, it would be possible to follow the instructions of
cant. Multiple nerves may be involved as in lepromatous the Operational Manual, Global Leprosy Strategy 2016 2020 on how to partly use
forms and there may be extensive nerve destruction as (MB-Child) blister packs for treatment.
MB, multibacillary disease; PB, paucibacillary disease.
in tuberculoid leprosy.

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 LEPROSY 735

PB leprosy (which was rifampicin and dapsone for
6 months) due to evidence indicating better clinical out-
comes with a three-drug, 6-month regimen. Published
studies for patients treated with the prior two-drug PB
regimen for 6 months showed that 2 to 44 percent of
patients had clinically active skin lesions at the end of
treatment. Nerve impairment occurred during treat-
ment in 2.5 percent of patients, and visible disabilities
increased from 4 percent at enrollment to 7 percent at 8
to 10 years of follow-up. Relapse rates ranged from 0 to
2.5 percent. For patients treated with the MB regimen
for 24 months, one study in Thailand found that 29 per-
cent of lesions were still active after 3 years and that visi-
ble disabilities increased from 5 percent at enrollment to
13 percent at 8 to 10 years of follow-up. Relapse rates
were low, from 0.15 to 0.2 percent, but several reports
have indicated much higher rates in subgroups of
patients with high bacteriologic indexes (BI . 4 1), usu-
ally occurring 5 to 7 years after treatment is stopped.
Relapsed patients responded to retreatment with the
same drug combination, indicating that the relapse
was not usually secondary to development of resistant
organisms. Viable bacteria have also been demon-
strated in patients who relapsed up to 13 years after
MDT for MB disease.
A retrospective survey of 40 documented patients who
relapsed showed that leprosy relapse after MDT usually
occurred late and all had new skin lesions. Most relapsed
with a positive skin smear after previously reaching nega-
tive BI status. The histologic features of relapsed BB-LL
patients included granulomas containing macrophages
or epithelioid cells, with sparse lymphocytes and acid-
fast bacilli. PB patients require 2 years, and MB patients
at least 5 to 10 years of monitoring after treatment.
It may be difficult, however, to differentiate clinically
between relapse, reactions, and recurrent infection.
Immunologically mediated reactions occurring after
completion of MDT are more frequent usually within
the year after treatment completion. In addition, there
may be persistent infection in nerves and eyes. DNA-
based PCR-positivity and the presence of acid-fast bacilli
by microscopic examination persist in some cases for
years after treatment but do not necessarily reflect myco-
bacterial viability.
A promising new assay of M. leprae viability has been
developed using 16S rRNA levels on skin biopsy speci-
mens and may assist in differentiating between relapse
and reactions after completion of MDT. Whole-genome
sequencing techniques have also revealed that patients
can be reinfected and did not relapse in recurrent lep-
rosy cases. Many clinicians in resource-rich countries
such as the United States have continued to use MDT
for 24 months for MB disease until definitive data
about relapses rates are available.
Side Effects of Multidrug Treatment
Although treatment with MDT is very effective, with
over 95 percent cure rates, medications may occasion-
ally cause serious adverse effects. The most common
adverse effects reported are for dapsone, and include
hemolytic anemia, methemoglobinemia, toxic hepati-
tis, photosensitivity, psychosis, and sulfone syndrome,
currently described as DRESS syndrome (drug reaction
with eosinophilia and systemic symptoms). Peripheral
neuropathies have been observed among patients using
dapsone in higher doses for dermatologic disorders.
They develop painless distal motor axonal degenera-
tion, most commonly involving the ulnar and median
nerves. Usually only motor nerve involvement is seen,
although sensory loss may also occur; this is usually
reversible when dapsone is discontinued.
Clofazimine has rare serious adverse effects; the most
common ones involve cutaneous hyperpigmentation
(the most common cause of discontinuation of this
drug), xerosis, ichthyosis, nausea, vomiting, diar-
rhea, and abdominal pain. In doses higher than
300 mg/day, clofazimine can be deposited in the intes-
tinal wall, causing acute gastrointestinal obstruction.
Rifampicin has been associated with toxic hepatitis,
thrombocytopenia, flu-like syndrome, respiratory fail-
ure, hemolytic anemia, shock, and renal insufficiency.
Drug Resistance and Treatment of Relapses
The worldwide prevalence of drug resistance to M. leprae
has not been established but reports from the WHO
indicate a low level of resistance in some relapsed cases.
Dapsone-resistant, rifampin-resistant, and multidrug-
resistant (MDR) leprosy have been reported in different
parts of the world, usually in association with relapse
after insufficient therapy. Primary rifampicin resistance
has also been reported, but clofazimine-resistant strains
have not been demonstrated. PCR-based DNA seq-
uence analysis of the rpoB gene of M. leprae, which is asso-
ciated with rifampin resistance (Table 41-4), presents a
cost-effective way for the study of drug resistance.
Dapsone resistance does not require a change of
therapeutic regimen. If rifampicin resistance is proven,
a WHO Expert Committee has recommended the
regimen to follow (Table 41-5). Rifampicin resistance

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736 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE

MXFX is identical to that of a single dose of rifampicin;

TABLE 41-4 ’ Mutations in Mycobacaterim leprae
Associated With Drug Resistance both killed 92.1 percent of the viable M. leprae. The
most promising new drug is bedaquiline, which is com-
Resistance Gene Percent Resistant in parable to rifampicin in potency but has an entirely
Drug Mutation Relapsed Cases
new mechanism of action and a long half-life. An inter-
Dapsone folp gene 5.9 national network of sentinel sites for drug-resistant lep-
rosy was established in 2007 to share data and technical
Rifampicin rpoB gene 4.1
expertise, including trends in development of new
Ofloxacin gyrA gene 1.2 drugs of relevance to leprosy.

remains rare except in Brazil; therefore standard WHO- LEPROSY REACTIONS

recommended MDT regimens remain the treatment
of choice for relapsed leprosy everywhere. But primary Leprosy reactions are immunologically mediated epi-
multidrug resistance to rifampin and dapsone can also sodes of acute or subacute inflammation that may occur
occur, as was described in a patient in the United States in any type of leprosy and result in increasing nerve
who originated in American Samoa. damage and worsening disability. The two main types
Quinolone resistance in M. leprae is an increasing of reactions are type 1 and type 2 reactions (also known
concern, especially in India; it may occur if ofloxacin is as erythema nodosum leprosum or ENL).8 There is cur-
used for other acute infections. High dropout rates rently no cheap, accurate diagnostic test to detect reli-
and a search for regimens with fewer side effects have ably leprosy reactions or to predict which patients will
led to trials with monthly rifampicin, ofloxacin, and develop these immunologic exacerbations, but various
minocycline (ROM). In a 2001 study, PB patients trea- research strategies aimed at identifying biomarkers to
ted with either ROM or MDT for 6 months had similar diagnose these reactions are being pursued.
cure rates of 97 percent. Both groups had similar
relapse rates after follow-up for 5 to 8 years, but the
rate of adverse effects was much lower in the patients
Type 1 Lepra Reactions (Reversal Reactions)
receiving ROM. Type 1 reaction is seen almost exclusively in the border-
Newer agents such as rifapentine (RPT) and moxi- line forms of leprosy (BT, BB, or BL) and is a manifes-
floxacin (MXFX), which are significantly more bacteri- tation of an improvement in the patient’s immune
cidal than rifampicin, may represent other therapeutic response to the infection, commonly as a result of treat-
alternatives. The bactericidal activity of a single dose of ment. The incidence of reversal reactions is highest 6
to 12 months after initiating treatment but reactions
may occur up to 5 years after diagnosis. They may be
TABLE 41-5 ’ Recommended Regimens for Drug-Resistant Leprosy
the presenting feature, especially during pregnancy or
Treatment after the initiation of antiretroviral therapy (ART) in
Resistance patients infected with human immunodeficiency virus.
Type First 6 Months (Daily) Next 18 Months (Daily) Clinical features of a type 1 reaction usually include an
acute worsening of the swelling and erythema of pre-
Rifampicin Ofloxacin 400 mg 1 Ofloxacin 400 mg OR existing skin lesions and development of acute, painful
resistance minocycline 100 mg 1 minocycline 100 mg 1
nerve palsies commonly involving the ulnar or pero-
clofazimine 50 mg clofazimine 50 mg
neal nerve. Histologic features of a type 1 reaction are
Ofloxacin 400 mg 1 Ofloxacin 400 mg 1 those of a delayed hypersensitivity response with CD41
clarithromycin 500 mg 1 clofazimine 50 mg lymphocytes, macrophages, and expression of IL-2 in
clofazimine 50 mg
the lesions. Intraneural caseous necrosis in tuberculoid
Rifampicin Clarithromycin 500 mg 1 Clarithromycin 500 mg OR disease and microabscesses in lepromatous disease can
and minocycline 100 mg 1 minocycline 100 mg 1
occur during reversal reactions. It is postulated that the
ofloxacin clofazimine 50 mg clofazimine 50 mg
resistance lysis of mycobacteria by antibacterial treatment causes
a release of antigen that mediates the immunologic

Ofloxacin 400 mg can be replaced by levofloxacin 500 mg OR moxifloxacin response. M. leprae antigens and a diffuse extracellu-
400 mg.
lar infiltrate have been found in macrophages and

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Schwann cells during reversal reactions, suggesting
that these antigens are initiating factors in the reac-
tion. Other studies indicate a strong Th1-like cyto-
kine profile within reactional lesions. TNF-α, which
has been shown to directly cause the destruction of
myelin and oligodendrocytes in vitro, is also overpro-
duced during reactions.
Corticosteroids are the treatment of choice for severe
type 1 reactions, especially those involving ulcerations
and neuritis.9 Severe neuritis is treated promptly with
prednisone at doses of 1 mg/kg daily, with increasing
doses if there is no response within 24 to 48 hours.
Corticosteroid therapy should be tapered slowly, espe-
cially in severe cases, to reduce the risk of relapse of the
neuritis. Studies have indicated that moderate doses
of corticosteroids given for 20 weeks are better than
high-dose corticosteroids for 12 weeks in reducing
the risk of relapse of neuritis. The approximately 60
percent success rate of corticosteroids in salvaging
nerve function in reversal reactions is related to the
promptness of initiation of therapy, as irreversible
damage can ensue within hours to days. Corticosteroids
have an immediate anti-inflammatory effect in reduc-
ing intraneural edema. More sustained benefit is prob-
ably due to its genomic effect, which affects cytokine
production at various levels. The principal mecha-
nism of action is thought to be inhibition of transcrip-
tion of TNF-α induced cytokine mRNA. A number
of cytokine genes have the same TNF-α binding sites
in their promoter regions, and corticosteroids down-
regulate the production of several proinflammatory
cytokines, including TNF, IL-2, and IFN-γ.
Occasional patients with severe, protracted reac-
tions require extended corticosteroid treatment for
several additional months due to severe nerve pain.
However, a Cochrane review of clinical trials has dem-
onstrated that prolonged corticosteroid regimens of
many months do not provide long-term functional
neurologic benefits for most patients.9 A more recent
multinational randomized controlled trial comparing
45 to 60 mg methylprednisolone daily for 20 weeks
versus 32 weeks for early (,6 months) nerve function
involvement showed 78 percent improvement in
both treatment arms. However, around 15 percent
of the patients (comprising significantly more MB
patients) in both groups required further individual-
ized treatment because of reactions or deteriorating
nerve function involvement, both of which occurred
primarily in the first few weeks after corticosteroid
treatment had ended. It appears that corticosteroids
should be started as early as possible with acute neuritis
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LEPROSY 737
but moderate doses should be continued for 20
weeks. Patients with higher BI should be monitored
closely for recurrent reactions or deteriorating nerve
function involvement for a few weeks after stop-
ping, as they may need resumption of corticosteroid
therapy.
Patients with pre-existing neuropathy have an
increased risk of nerve function involvement and
reversal reactions with treatment and this is not pre-
vented by prednisone in the first 4 months of MB
treatment. In contrast, a strong protective effect on
neuritis was observed in those without significant
loss of nerve function during the 4 months of pro-
phylactic corticosteroid treatment and MDT, but
this was not sustained at 1 year. Multiple or large
lesions on the face overlying the distribution of the
facial nerve may therefore benefit from low-dose
prophylactic corticosteroids at the onset of MDT to
prevent facial palsy, lagophthalmos, and ensuing
exposure keratitis. Both cyclosporine and azathio-
prine have also been tried with varying success for
their steroid-sparing effect. Corticosteroids have to
be used in the first 5 days in patients treated with
cyclosporine, until this drug reaches a steady state.
Acute neuritis in reversal reactions that have not
responded to high-dose corticosteroids for 6 weeks
may be considered for surgical decompression (neu-
rolysis) to relieve the pressure and preserve function,
although there have been no large-scale controlled
studies of this modality of treatment. Thalidomide
has not been successful in the treatment of reversal
reactions, perhaps because T-cell activation appears
to be a significant component of reversal reactions
and thalidomide stimulates T-cell activation.
Type 2 Reactions
ENL reactions occur almost exclusively in patients at
the lepromatous end of the spectrum (BL and LL)
and continue to be the most common cause of hospi-
talization. They usually occur within 2 years of the start
of therapy, but rarely may be the presenting symptom.
Risk factors for ENL reactions include antibacterial
therapy, female sex, pregnancy, and high bacterial
loads. Clinically, presentation is with crops of new
painful erythematous papules that may resolve sponta-
neously. Other features include severe fatigue, fever,
acute neuropathy, lymphadenopathy, uveitis, orchitis,
mastitis, periostitis, and glomerulonephritis. Laboratory
tests may reveal anemia, leukocytosis, and abnormal
738 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE
liver function tests. In contrast to type 1 reactions,
patients tend to develop chronic recurring bouts of
ENL reactions. In the MDT era, ENL occurs in 16 to
47 percent of LL patients and 2 to 11 percent of BL
patients. ENL reactions are thought to be associated
with the release of M. leprae antigens from dead and
dying bacilli, inducing humoral immune mechan-
isms and immune complex formation, accompanied
by high levels of circulating concentrations of TNF.
These complexes result from an antigen antibody
reaction involving activation of the complement
system and may resemble the Arthus phenomenon,
resulting in systemic vasculitis and panniculitis.
The management of ENL is aimed at controlling
the acute inflammation and neuritis, providing pain
relief, saving vision, and preventing further attacks. Mild
symptoms in the absence of neural and ophthalmo-
logic symptoms may be treated with comfort measures
and nonsteroidal anti-inflammatory drugs. Clofazi-
mine at high doses up to 300 mg per day, with slow
tapering over a year, can be effective for more severe
cases of ENL without neural involvement. The drug of
choice for treating the severe systemic symptoms associ-
ated with ENL is thalidomide. This drug accelerates
the degradation of mRNA encoding TNF-α, resulting
in its decreased production by monocytes and macro-
phages, without significantly reducing the production
of other monocytic cytokines. Fever, fatigue, and skin
lesions respond within a few days to thalidomide but
neuritis accompanying ENL may take up to a week to
respond.
Corticosteroids, with their more rapid effect in reduc-
ing intraneural edema, are often added to treat severe
neuritis and prevent further nerve damage. High-dose
pulse dexamethasone and azathioprine have been uti-
lized in cases of recurrent ENL unresponsive to stan-
dard prednisone therapy. Successful treatment with
methotrexate, in corticosteroid- and thalidomide-
resistant ENL has also been reported. Methotrexate
exerts anti-inflammatory and immune-suppressive
effects.10 It has direct inhibitory effects not only on the
proliferation of cells involved in inflammatory reac-
tions but also on proinflammatory cytokines. The
immunomodulatory activity of thalidomide mainly lies
in its capability to alter the secretion and activities of
various cytokines including iL-6, IL-10, IL-1, and TNF-α;
these cytokines are also targeted by methotrexate.
The newer TNF-α blockers such as infliximab have
been reported to precipitate the development of clini-
cal symptoms in latent leprosy in some patients with
rheumatoid arthritis. Chronic steroid-dependent ENL
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has also been found to be due to rifampin resistance
and responded to an alternate regimen of minocy-
cline, ofloxacin, and clofazimine.11
In addition to severe teratogenicity, which limits its
use in women of child-bearing age, thalidomide may
cause an axonal, length-dependent, sensorimotor neu-
ropathy which presents with painful paresthesias or
numbness. The incidence rate is maximal during the
first year of treatment and is dose dependent.
In a study in which patients underwent neurologic
examination and nerve conduction studies during
treatment, thalidomide-induced neuropathy was seen
in 25.2 percent of patients. The risk of neuropathy was
highest when the daily dose exceeded 75 mg. No neu-
ropathy was observed when daily doses of less than
25 mg were used. A recent review of the literature from
1965 to 2017 found thalidomide toxicity in less than
5 percent of patients.12 Sural nerve biopsies have
shown evidence of Wallerian degeneration and loss
of myelinated fibers in thalidomide toxicity. Moni-
toring sensory nerve action potential amplitudes by
nerve conduction studies may be useful for the early
detection of thalidomide neuropathy, a decline in
amplitude of 40 percent compared to the baseline
usually being associated with clinical symptoms of
neuropathy. Monitoring F waves may also be useful
to detect early thalidomide neuropathy; F-wave chrono-
dispersion may occur before changes in sensory ampli-
tudes. Other adverse effects associated with thalidomide
include deep venous thrombosis in 14 percent of
patients.
LEPROSY AND HUMAN IMMUNODEFICIENCY
VIRUS INFECTION
The interaction of leprosy and HIV coinfection is an
evolving picture and has been significantly impacted by
more widespread ART.13 HIV affects cell-mediated
immunity, and it was initially thought that the decrease
in CD4 cells may result in an increase in disseminated
leprosy. However, to date there are no clinical data to
suggest that leprosy may worsen HIV infection or that
HIV infection increases the risk of leprosy. All types of
leprosy have been reported in HIV-infected patients,
suggesting that HIV infection does not increase the
rate of lepromatous disease. Coinfected patients trea-
ted with standard-length WHO-MDT regimens have
responded adequately but in one study a 3.4 percent
relapse rate occurred in coinfected patients compared
to 1.0 percent in HIV-negative patients. This suggests

that patients with coinfection should be monitored
more closely for relapse after treatment. There are
some data in coinfected patients that suggest that they
may be at a higher risk of developing acute and recur-
rent reactions, especially when they are on ART.
In 1995, before widespread ART use, patients with
AIDS and BT leprosy had lesions with well-formed
granulomas and normal CD4 cell numbers in their
lesions even though they had low circulating CD4
counts. Coinfected patients with LL had lesions with
loose infiltrates comprising heavily parasitized macro-
phages and a small number of almost exclusively
CD8 lymphocytes, which was similar to HIV-negative
patients.
When a coinfected cohort treated with ART was fol-
lowed prospectively, BT leprosy was the most common
clinical form studied. Coinfected patients who present
with BL leprosy and AIDS may shift to BT disease after
implementation of ART and MDT, which suggests that,
in some patients, granuloma formation might be altered
by an ART-induced increase in the CD41 T-cell count.
Histopathologic follow-up of these patients has revealed
that on initiation of ART and MDT foamy histiocytes
containing numerous acid-fast bacilli are replaced by
granulomas consisting of lymphocytes and epitheli-
oid cells with scant or no acid-fast bacilli. These find-
ings demonstrate the true impact of HIV infection,
ART, and MDT on leprosy granuloma formation.
Immunostaining techniques revealed the absence
of CD41 T cells in all granuloma specimens from the
patients with BT disease, but CD3 1 T cells, macro-
phages, and natural killer cells were observed within
the granulomas. These observations indicate that
cell types other than CD4 1 and CD8 1 T lympho-
cytes may be playing a role in granuloma formation
under the conditions observed for individuals with
leprosy and HIV infection receiving ART. Further stud-
ies aiming to investigate this possibility are currently
ongoing.
Another consequence of ART-induced CD41 T-cell
count improvement is the development of immune
reconstitution inflammatory syndrome (IRIS). IRIS is
a paradoxical deterioration in clinical status after
starting ART, a deterioration that is attributable to
the recovery or reactivation of the immune response
to a latent or subclinical process. This syndrome was
first associated with leprosy in 2003 and usually devel-
ops within 6 to 10 months after initiating ART. Risk fac-
tors include advanced HIV disease with CD4 counts
below 50 before ART. BT leprosy was the commonest
form detected and type 1 (reversal) reaction was always
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LEPROSY 739
present. Ulceration, a highly unusual feature in leprosy
lesions, was commonly observed.
The neuropathies associated with HIV have been
well described. A few small studies in the 1990s did
not find increased nerve damage in coinfected
patients. Subsequently it was found that leprosy
patients coinfected with HIV (87% on ART) when
compared to patients with leprosy alone had a greater
rate of overall nerve function involvement, especially
in MB disease. The most frequent onset of leprosy in
relation to ART was within 12 months of the introduc-
tion of therapy. Nerve function involvement improved
over time using MDT and ART. Neuritis was treated
with prednisone at doses recommended by the WHO,
and coinfected patients had the highest rate of clini-
cal improvement in the first 60 days.
PREVENTION
Prevention of leprosy with vaccines directed against
M. leprae or other mycobacterial antigens has thus far
not proved to be too effective in large-scale clinical trials.
BCG appears to be protective against leprosy in some
populations but not in others. Repeated doses of BCG
vaccine may be more effective, but this approach has
limited clinical application, because of the cost of
implementation and the potential for adverse reac-
tions in immunosuppressed patients. Mapping of
the M. leprae genome and the discovery of the arma-
dillo as a good animal model for leprosy pathogene-
sis have led to better understanding of immunology
with potential for identification of candidate anti-
gens for vaccine development.
LepVax, a defined subunit vaccine that provides effec-
tive pre-exposure and postexposure prophylaxis of
M. leprae infection, is in early clinical trials.14 It appears
safe and, unlike BCG, alleviates and delays the neuro-
logic disruptions caused by M. leprae infection. MDT
does not eliminate transmission in households, and
early detection of subclinical leprosy or the carrier state
is difficult. The identification by PCR (or other meth-
ods) of high-risk household contacts who may benefit
from vaccination or chemoprophylaxis deserves fur-
ther study. The 2018 WHO guidelines recommend
the use of single-dose rifampicin as preventive treat-
ment for adult and child (2 years of age and older)
who are close contacts of leprosy patients, after exclud-
ing leprosy and TB disease.15 This is based on the
COLEP2 randomized controlled trial that found
single-dose rifampicin in leprosy contacts led to a
740 AMINOFF’S NEUROLOGY AND GENERAL MEDICINE
57 percent reduction in the risk of leprosy after 2
years and 30 percent after 5 to 6 years.
CONCLUDING COMMENTS
The discovery that demyelination can be induced by
dead M. leprae or its bacterial cell wall alone, both
in vitro and in vivo, and the use of armadillos as animal
models to study the pathogenesis of nerve damage
have provided new insights into the underlying causes
for continuing neurologic injuries in patients who have
been bacteriologically cured of leprosy after MDT.
Leprosy will continue to occur in endemic and nonen-
demic countries where physicians are becoming less
familiar with the clinical presentation of a disease for
which early diagnosis and MDT treatment are crucial
to prevent new and ongoing nerve damage. Success-
ful application of modern molecular methods using
current knowledge of the bacterial genome and host
susceptibility factors, should lead to better identifica-
tion of target M. leprae antigens for improved diagnos-
tic testing, vaccine development, identification of new
antimicrobial agents, and detection of relapses after
therapy. An improved understanding of nerve dam-
age and reactions should lead to better preventive
and therapeutic modalities.
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