Morbus Hansen= Kusta=Lepra

Indonesia termasuk 1 dari 9 negara dengan endemisitas kusta

tertinggi di dunia menurut WHO sekaligus menjadi peringkat
ke-3 penderita kusta terbanyak setelah India dan Brazil. Pada
tahun 2009, prevalensi penyakit kusta di Indonesia tercatat
sebesar 21.026 kasus (0,91/ 10.000) dan berhasil memenuhi
kriteria eliminasi kusta yaitu 1 per 10.000 penduduk. Angka
prevalensi kusta tersebut menurun pada tahun 2010 menjadi
20.329 kasus (0,86/ 10.000).

Definisi: infeksi kronis pada manusia yang disebabkan

M. lepra, t.u menyerang kulit dan saraf perifer
 Epidemilogi

Cara penularan belum diketahui secara pasti, diduga kontak

kulit langsung dalam waktu lama
Terjadi penularan ada 3 faktor:
a. Jalan keluar dari penderita t.u sekresi lendir hidung
b. Cara penularan sendiri: kulit>kulit; percikan udara
pernapasan, melalui tr gastrointestinal,
c. Pintu masuk kuman (port dentry)
 Etiologi & Klasifikasi

M.leprae ditemukan oleh G.A. Hansen thn 1874 di Norwegia,

belum dapat dibiakkan dalam media artifisial. Bentuk basil
ukuran 3x8x0,5 m bersifat tahan asam dan alkohol, gram
positif.
Kepentingan klasifikasi:
a. Identifikasi kasus yang infeksius
b. Identifikasi kasus yang mungkin infeksius
c. Identifikasi penderita yang mungkin mengalami deformitas.
d. Menentukan lama R/
Klasifikasi
Madrid (1953) Ridley & Jopling (1966)
Tipe lepromatus A Tipe TTstabil
Tipe tuberkuloid B. Tipe BT
Tipe borderline C. Tipe BB
Tipe indeterminant D. Tipe BL

Untuk kepentingan E. Tipe LL

penelitian dan Dasar: respon imonologis
pemberantasan
 Hubungan pengklasifikasian
tersebut
TT BT BB BL LL

Tuberkuloid Borderline Borderline Lepra Lepra

matosa matosa
Polar Indeterminan indetermi Polar Polar
Tuberkuloid nan leproma
tosa
Non basiler basiler
Patogenesis

Kontak dengan M.lepraeinfeksi subklinis

sembuh alamiah. M leprae mempunyai
patogenesis dan daya invasif yg rendah.
Respon imun yg berbeda menimbulkan
ketidak-seimbangan derajat infeksi dengan
penyakit.
Peny Kusta dapat disebut peny imunologik.
Gambaran klinis dan histologis

1. Indeterminat
1 atau lebih makula hipopigmentasi
Batas tidak tegas, sedikit kering
Gangguan gungsi keringat<
Ganggauan sensibilitas <
Basil lepra <<
2.Tipe tuberkuloid
Lesi kulit <, bahkan hanya 1 buah
Makula hipopigmentasi/ eritematosa
Batas tegas, kadang tepi meninggi, tengah
menipis, permukaan kasar dan kering
Gangguan sensibilitas lengkap/ tidak
lengkap
Dijumpai penebalan syaraf pada daerah lesi
3. Tipe lepromatous
Bentuk ekstrim dimana penderita tidak mampu
melawan infeksi
Makula multipel sedikit hipopigmentasi
Papula infiltrat, agak berkilat
Noduler, simetris di seluruh tubuh.
Gangguan sensibilitas belum muncul pada awal
Std akhir terjadi anestesi dan sekuele saraf
bilateral, madarosis, ulserasi nasal, ginekomasti,
orchitis, fasies leonina
4. Tipe Borderline
Tidak menunjukkan invasi kuman pada mukosa
hidung, mata, tulang, maupun testis
Lesi di kulit >>, ttp tidak sebanyak lepramatosa
Plak eritematosa, iregular, tepi samar-samar
Didaerah tengah ada penyembuhan (punch out)
Diluar plak didapat lesi satelit
Saraf banyak terkena, tidak simetris
5. Tipe Borderline tuberkuloid

Lesi mungkin = kulit yang normal, mungkin

terdapat satelit. Lebih banyak dari
tuberkuloid, lebih variatif, deskuamasi.
PA: adanya zona jernih (grenz zone) di
daerah sub epidermis, tanda khas tipe ini.
Indek bakteri menunjukkan BTA antara 0-
+2.
6. Borderline lepromatous
Lebih pleomorfik, >,
tersebar
Lesi dengan tanda
punched out masih
dijumpai
Madarosis, belum
dijumpai atau
sebagian. Lesi seperti
lepramatosa, hanya
tidak simetris
Diagnosis

Ditegakkan dengan pemeriksaan klinik dan bakteriologik

Tanda kardinal: anestesi terjadi pada kulit daerah
inervasi syaraf. Tes sensibilitas perlu dilakukan
Penebalan syaraf setempat, sering disertai kelemahan
otot yg diinervasi, terjadi atrofi + anhidrosis
Lesi kulit: makula papula, nodulus, infiltrat yg timbulnya
tidak diketahui, mula gatal kemudian anestesi
tetapilambat
BTA. DX ditegakkan jika dijumpai 3 tanda kardinal
pertama, kuat bila + tanda yg ke 4.
Pembantu diagnosis
1. Pemeriksaan bakteriologis
Kerokan kulit atau mukosa hidung
Dihitung Indeks bakteri dan indeks morfologi. IB 0-
+6. IM merupakan prosentase kumat berbentuk solid.
IM berguna untuk a. mengetahui infeksius penderita,
b. resistensi kuman terhadap R/ c. Keadaan
penderita.
2. Pemeriksaan PA.
3. Tes histamin
4. Tes lepromin.
Terapi

Farmakologi:
MDT, paling banyak dipakai dan paling murah.
Dosis Rifampisisn 600mg/ bulan, DDS 100
mg /hari; klofasimin 300 mg/ bulan ditambah
50 mg setiap hari.
Non farmakologi
Rehabilitasi
TUBERKULOSIS KUTIS

Peny kulit yang disebabkan Mycobacterium

tuberculosis, M bovis dan kadang kadang
vaksin Bacillus Calmette-Guerin
M. tuberculosis merupakan kuman aerob,
tahan asam, intraselular fakultatif, bentuk
batang, lebih halus dibanding M.leprae
 Patogenesis
Cara infeksi ada 6 macam :
1. Penjalaran langsung ke kulit dari organ di bawah kulit yang telah

dikenai penyakit tuberkulosis, misalnya skrofuloderma.

2. Inokulasi langsung pada kulit sekitar orifisium alat dalam yang dikenai
penyakit tuberkulosis, misalnya tuberkulosis kutis orifisialis.
3. Penjalaran secara hematogen, misalnya tuberkulosis kutis miliaris.
4. Penjalaran secara limfogen, misalnya lupus vulgaris.
5. Penjalaran langsung dari selaput lendir yang sudah diserang penyakit
tuberkulosis, misalnya lupus vulgaris.
6. Kuman langsung masuk ke kulit yang resistensi lokalnya telah
menurun atau jika ada kerusakan kulit, contohnya tuberkulosis kutis
verukosa.
Epidemiologi

Penularan melalui inhalasi, ingesti dan

inokulasi
Distribusi insidensi pasti tidak diketahui, di RS
1-4 %. TBC kutis yang paling sering dijumpai
pada dekade 1-2 yaitu tbc kutis verukosa
Patogenesis

Kuman masuk multiplikasi intraseluler reaksi

jar leukosit dan sel mononuklearterbentuk
granuloma epiteloid, disertai nekrosis kaseasi.
Faktor yang mempengaruhi respon kulit: a,
sifat kuman, b. respon imun tubuh c. cara
masuk kuman, d perbedaan spesies e.
virulensi, f. jumlah kuman
Respon imun pada infeksi

Peran imunitas selular.

Spektrum klinis tergantung respon imun tubuh
sehingga dibagi menjadi 2 kutub yaitu: kutub
reaktif dan kutub anergik.
Kutub reaktif: banyak sel limfosit T, granuloma
epiteloid, nekrosis perkejuan ditengah, <
organisme
Kutub anergik: > m.o, sel makrofag
 1. KLASIFIKASI

1. TUBERKULOSIS SEJATI
Primer: 1. Tbc chancre, 2. Tbc milier
Sekunder: 3. Lupus vulgaris 5. Skrofuloderma
4. Tbc kutis verukosa 6. Tbc kutis
orifisialis
II. TUBERKULOID
Papular1. Tuberkulid papulonekrotik Nodular
2. Liken skrofulosorum 3. Eritema
induratum
Gambaran klinis

Tuberkulosis sejati
1. TBC Chancre (kompleks primer tb)
Terjadi pd orang yg belum pernah terinfeksi
Masuk melalui abrasi kulit, trauma kecil.
Lokasi: muka & anggota badan
UKK: papul & nodul kecoklatanpecahulkus
indolen, tepi menggaung. Limfadenitis. Tes
tuberkulin mula-mula (-)-- +
2. Tbc miliar

Perluasan hematogen dengan imunitas jelek

Bayi/ anak-anak. Primer di paru/ meninges
Klinis: mendadak tersebar seluruh tubuh,
papula vesikel, pustula, adanya krusta bila
diangkat umbilikasi. Tuberkulin (-)
PA: menunjukkan adanya fokal nekrosis dan
abses dikelilingi zona makrofag, > BTA
Lupus vulgaris
Imunitas baik dan pernah terinfeksi
Perluasan hematogen/ limfogen
> pada wanita
UKK: plak eritem /kecoklatan, diatas terdapat
papul tersebar berwarna kuning, diaskopik : apple
jelly. Ditusuk papel akan kempes
Predileksi: pada hidung, telinga, pipi, pantat,
jarang di badan.
 TB kutis verukosa

Infeksi eksogen pada individu

dengan imunitas baik. Pd orang
yg kontak dengan bahan/ hewan: dr. drh
Perjalanan kronik> UKK nodul kemerahan,
tunggal->multipel, permukaan kasar-verukosa.
Klinis lesi terdiri atas 3 bagian: halo
hiperpigmentasi di perifer, peninggian dengan
pustula dan zona verukosa atau atrofi di tengah.
Predileksi: tangan, lutut, siku, kaki.
Skrofuloderma
(TB colliquativa cutis)

Perluasan langsung dari

tb kelenjar limfe, tulang
atau sendi
Kronik dan sering kambuh
Satu nodul indolen, keras dan dalam,
melekat pada kulit, beberapa minggu lesi
menjadi kemerah-merahan, melunak dan
supurasi, pecahmembentuk sinus/
ulkus. Sembuh dengan sikatrik. BTA >>
Lokasi: leher,
supraklavikuler,
aksila, inguinal,
umumnya
unilateral.
TB kutis orifisialis
Terjadi pd mukosa atau kulit disekitar orifisium
karena autoinokulasi, perluasan limfogen/
hematogen
Predileksi: mulut, sekitar anus dan genitalia.
Mulai dengan nodul eritem dan edem, pecah
jadi ulkus dangkal, menggaung dan nyeri, Lnn
regional membesar
TUBERKULID
Sembuh sendiri, BTA pada lesi (-), tes tuberkulid +++
Papulanekrotik: simetris pada ekstensor anggota
badan, nekrosis disentralkrusta lengketsembuh
dengan meninggalkan jar sikatrik
Liken skrofulosorum: erupsi likenoid, pd anak-anak
dengan riwayat tb paru. UKK papula kekuning-
coklat,permukaan datar dan asimtomatik
Eritema induratum; > pd tropis, wanita muda,
predileksi tungkai kaki bawah, nodul pecah ulkus
tidak teratur sembuh jar sikatrik.
 Diagnosis & Terapi
Anamnesis riwayat tbc, pemeriksaan klinis umum
dan dermatologis. Dx ddukung laboratorium,
pemeriksaan BTA dan usapan jar langsung, biakan
dan PA.
Diagnosis pasti tuberculosis kutis tidak dapat
ditegakkan berdasarkan tes tuberculin yang positif
karena tes ini hanya menunjukkan bahwa penderita
pernah terinfeksi tuberculosis tetapi tidak dapat
membedakan apakah infeksi tersebut masih
berlangsung aktif atau telah berlalu.
 Terapi

Terapi: Kombinasi
INH,
rifampisin,
ethambutol
streptomisin,
pyrazinamide.
Pengobatan sama
seperti tbc paru.
Terapi
 Leprosy (Hansen's disease)

Leprosy (Hansen's disease) can be defined as a

chronic granulomatous infection and its sequelae,
caused by Mycobacterium leprae, and affecting
primarily skin and nerves.
Leprosy is an important clinical problem, with more
than 600,000 new cases yearly, worldwide.
 Also, despite apparently curative antibacterial
therapy, one-quarter to one-third of all patients will
have a debilitating and permanent neurologic deficit.
Because of its diverse host responses, for clinicians,
leprosy is a challenging diagnostic problem, and for
immunologists, it is an exemplary model for
understanding CMI in humans.
 HISTORICAL ASPECTS

Leprosy is an ancient disease; sacred writings from India in

the sixth century B.C. give a good description of a similar or
identical illness. Greek soldiers returning from Asia in third
century B.C. are thought to have introduced the disease into
Europe.
Stigmatization of patients with leprosy remains an unfortunate
but enduring legacy of the European pandemic (1000 to 1500
A.D.).
Hansen's attribution of M. leprae as its etiologic agent in 1873
marks the beginning of scientific leprology.
 Effective chemotherapy began with the introduction
of sulfones in 1943.
The limited growth of M. leprae in the mouse foot
pad, in 1961, provided a way to screen for
therapeutic agents and to identify drug resistance.
Rifampin, in 1970, was the first drug to be identified
as bactericidal for M. leprae and is now the
cornerstone of most therapeutic regimens.
 In 1919, the lepromin skin test inaugurated
systematic study of host resistance as the source of
disease diversity, lymphocyte transformation tests
being established in the 1960s as an in vitro
correlate.
The recognition of leprosy in the nine-banded
armadillo, in 1971, provided a source of large
quantities of highly purified M. leprae for a wide
variety of investigations, culminating in the
sequencing of the entire genome of M. leprae in
2001.
This landmark achievement will provide novel
avenues of investigation, which, in turn, will provide
new methods of intervention.
The recognition of leprosy in the nine-banded armadillo, in 1971,
provided a source of large quantities of highly purified
M. leprae for a wide variety of investigations,
culminating in the sequencing of the entire genome of M. leprae
in 2001.
 EPIDEMIOLOGY

Leprosy, primarily a disease of developing countries,

is endemic in all continents, except Antarctica.
In the Americas, only Canada and Chile are not
endemic areas, with Texas and Louisiana being
endemic states in the United States. The southern-
most nations of Europe have a very low incidence,
while leprosy is endemic in many Pacific islands.
The Indian subcontinent has two-thirds of the world's
leprosy burden.
 The highest case detection rates are in India, Brazil,
Madagascar, Nepal, and Tanzania.
During the decade of the 1990s, the prevalence of
leprosy fell by 90 percent, because patients
completing a course of multiple-drug therapy have
been considered to be cured, but the incidence of
the disease has remained unchanged.
 In all populations studied, lepromatous disease is more
common in men than in women by a 2:1 ratio. The tuberculoid
form dominates wherever the disease is common.
The median age of onset is less in tuberculoid than in
lepromatous patients, but in both groups, leprosy is
predominantly a young person's disease, the majority of
cases occurring before age 35 years.
However, age is not protective; new cases of each type occur
in the eighth and ninth decades of life. The incubation time for
tuberculoid leprosy is up to 5 years and for lepromatous may
be 20 years or longer.
 The preponderance of opinion supports the traditional view
that M. leprae is transmitted from human-to-human, but the
presence of an M. leprae caused lepromatous-like illness in
wild armadillos, evidence of armadillo exposure as a risk
factor for leprosy in people, and the presence of an M. leprae-
like organism on sphagnum moss, suggest that nonhuman
sources for M. leprae may be important.
The route of infection is unknown, but current evidence favors
respiratory transmission; evidence for congenital and
percutaneous transmission has been presented, but these are
probably rare.
In leprosy endemic areas, subclinical infection is common, as
judged by serologic studies identifying M. leprae-specific
antibodies.
 ETIOLOGY AND PATHOGENESIS

M. leprae, the cause of leprosy, is a noncultivable,

gram-positive, obligate intracellular, acid-fast
bacillus.
The union of bulk extracted M. leprae from
armadillos with the techniques of molecular biology
has proven to be a fruitful marriage, its crowning
accomplishment being the sequencing the bacillary
genome.
 The genome of M. leprae (3.27 megabases) is notably shorter
than that of M. tuberculosis, (4.41 megabases).
Even more striking, the M. leprae genome codes for 1600
genes, M. tuberculosis codes for 4000.
The two species share 1439 genes in common. In M. leprae
only one-half of its genome is coding sequence, this evident
gene deletion and decay leaving M. leprae with few
respiratory enzymes, but offering a reasonable explanation for
the failure to cultivate the organism in cell-free media, as well
as for its obligatory intracellular environment.
 The bacillary cell wall consists of a peptidoglycan backbone linked to
arabinogalactan and mycolic acids. Immunogenic proteins are associated
with the cell wall, and also present in the cytoplasm.
These include highly conserved heat shock proteins of molecular weight
10, 65, and 70 kDa, each bearing species-specific and cross-reacting
epitopes. A lipoglycan target of both antibody and cellular immune
responses, lipoarabanomannan, courses through the outer membrane
and inserts into the cell membrane.
Phenolic glycolipid I is a major, species specific and immunogenic,
constituent of the highly nonpolar outer layer of the bacillus. Entry into
nerves is mediated by the binding of the species-specific trisaccharide in
phenolic glycolipid I to laminin-2 in the basal lamina of Schwann cell-axon
units, providing a rationale as to why M. leprae is the only bacterium
known to invade peripheral nerves.
 The biopsy index (BI),
In tissues or smears, M. leprae is quantified by the biopsy
index (BI), a logarithmic scale as to the numbers of bacilli per
oil immersion field (OIF):
a BI of 6 is 1000 or more bacilli/OIF;
a BI of 5 is 100 to 1000/OIF;
a BI of 4 is 10 to 100/OIF;
a BI of 3 is 1 to 10/OIF;
a BI of 2 is 1 bacillus/1 to 10 OIFs;
a BI of 1 is 1/10 to 100 OIFs;
and a BI of 0 is no bacilli in 100 OIFs.
 GENETICS

A twin study has provided compelling evidence that both

genetic and environmental factors are important in
determining disease susceptibility and disease expression.
The recent report of a susceptibility locus for leprosy in India,
located on chromosome 10p13, may be the beginning of
going beyond the vague rubric of polygenetic susceptibility.
Major histocompatibility complex class II antigens appear to
influence disease expression, that is tuberculoid versus
lepromatous, but not susceptibility.
 PREVENTION
To control leprosy by vaccination usually consists of BCG
alone, viable BCG in combination with killed M. leprae, or
killed M. leprae alone.
Most studies support a reduction in leprosy incidence, roughly
one-third in tuberculoid cases, considerably less in
lepromatous.
The recent observation that lipid and lipoglycan antigens are
presented to T cells (CD4, CD8, CD3+) by CD1+ cells
opens the door to entirely new vaccination protocols.
Other preventive measures, such as isolation of patients or
treatment of patient contacts with antimicrobials, have been
disappointing.
 CLINICAL MANIFESTATIONS

The diverse clinical manifestations of leprosy can be

reduced to two kinds of changes,
a granulomatous spectrum
the reactional states.
 A Granulomatous Spectrum

The most detailed description of the granulomatous

spectrum of leprosy came from Ridley and his
associates, integrating both clinical and histologic
changes.
Ridley's construct is a six-member granulomatous
spectrum, ranging from high to low resistance, TT
(polar tuberculoid), BT (borderline tuberculoid), BB
(borderline), BL (borderline lepromatous), LLs
(subpolar lepromatous), and, finally, LLp (polar
lepromatous):
 Conceptually, TT and LLp are clinically stable, but, between
the poles, the hosts granulomatous posture may change, as
indicated by the arrows, upgrading (or reversing) to a posture
of higher resistance, often with devastating inflammation, or
downgrading to a posture of lower resistance, usually silent
but occasionally inflammatory.
BT patients may upgrade to TT, thus, becoming stable, but
LLs patients do not downgrade to LLp nor do LLp patients
upgrade.
Putatively, the host's granulomatous posture is the result of
the degree of cell-mediated immunity directed against M.
leprae.
 In comparison of pre-Ridley and Ridley terminology,
tuberculoid corresponds to TT and BT, borderline or dimorphic
to BB and BL, and lepromatous to LLs and LLp. In virtually all
TT patients, and in most BT cases, acid-fast bacilli cannot be
found, whereas in BB, BL, LLs, and LLp, bacilli are
demonstrable with ease.
Ridley's construct is useful in classifying patients, especially
for immunity.
Another classification system is useful for treatment:
paucibacillary, that is to say no acid-fast bacilli found, or
multibacillary, that is to say one or more bacilli found.
 Peripheral Nerve Changes
Four types of peripheral nerve abnormalities are common in leprosy:
(1) nerve enlargement (usually perceived as asymmetry), particularly in
those close to the skin, such as the great auricular, ulnar, radial
cutaneous, superficial peroneal, sural and posterior tibial;
(2) sensory loss in skin lesions;
(3) nerve trunk palsies either with signs and symptoms of inflammation or
without such overt manifestations, that is, silent neuropathy, usually with
both sensory and motor loss (weakness and/or atrophy) and, if long-
standing, also with contracture; and
(4) acral distal symmetric anesthesia, a withering away, so to speak, of
the type C fibers, involving heat and cold discrimination before loss of
pain or light touch, beginning in acral areas and, over time, extending
centrally but sparing the palms, at least for a while.
 Uncommon peripheral nerve abnormalities include
nerve abscesses (palisading granulomas formed
about cutaneous sensory nerves) and the carpal
tunnel syndrome.
Anhidrosis is a common manifestation of
sympathetic nerve involvement.
 POLAR TUBERCULOID LEPROSY

In TT, immunity is strong as manifested by spontaneous cure

and the absence of downgrading to a posture of less host
resistance.
The primary skin lesion of TT is a plaque, often assuming an
annular configuration secondary to peripheral propagation
and central clearing.
The border of the plaque or both borders of the annulus are
sharply marginated.
Typically, the lesion is firmly indurated, elevated,
erythematous, scaly, dry, hairless, and hypopigmented, but
clinically, considerable variation is encountered.
 A nearby sensory nerve may or may not be enlarged,
but the lesion itself is characteristically anesthetic
and anhidrotic.
Skin lesions are often solitary, particularly in those
patients who are TT de novo, as contrasted to those
who upgrade to TT from BT, where multiple lesions,
usually no more than three, may be found. In both
groups, immunity is sufficient to effect cure, thus,
placing an upper limit of 10 cm on lesion size, but
antibiotic therapy is recommended.
 BORDERLINE TUBERCULOID
LEPROSY

In BT disease, immunologic resistance is strong

enough to restrain the infection, in that the disease is
limited and bacillary growth retarded, but the host
response is insufficient to self-cure.
These patients are somewhat unstableresistance
may increase, upgrading to TT, or decrease,
downgrading to BL.
 The primary skin lesions of BT are plaques and papules. As
in TT, an annular configuration is common and both borders
are sharply marginated but annular lesions or plaques may
have satellite papules.
Hypopigmentation may be conspicuous in darkly pigmented
patients. In contrast to TT, typically, there is little or no
scaling, less erythema, less induration, and less elevation,
but lesions may become much larger, that is, well over 10
cm in diameter, a single lesion sometimes involving an
entire extremity over time.
Multiple, asymmetric lesions are the rule, but solitary lesions
are not rare.
 Loss of sensation in skin lesions is the rule and
nerve trunk involvement, enlargement, or palsies,
usually in no more than two and asymmetric, are
common.
Nerve abscesses, when they occur, are most often
seen in males with BT disease.
 BORDERLINE LEPROSY BB
is the immunologic midpoint or mid-zone of the
granulomatous spectrum, being its most unstable area, with
patients quickly up- or downgrading to a more stable
granulomatous posture with or without a clinical reaction.
Characteristic skin changes are annular lesions with sharply
marginated interior and exterior margins, large plaques with
islands of clinically normal skin within the plaque, giving a
Swiss cheese appearance, or the classic dimorphic lesion.
Because of instability, the BB posture is short-lived and such
patients are evidently rarely seen; for example, we have yet to
see a nonreactional patient meeting both clinical and
histologic criteria.
 BORDERLINE LEPROMATOUS
LEPROSY

.
In BL disease, resistance is too low to significantly restrain
bacillary proliferation, but still sufficient to induce tissue
destructive inflammation, especially in nerves. Thus, patients
with BL may have the worst of both worlds. The BL category
is highly variable in its clinical expression.
Although seen in only a third of BL patients, the classic
dimorphic lesion is the most characteristic, having an annular
configuration with a poorly marginated outer border
(lepromatous-like) but a sharply marginated inner one
(tuberculoid-like, hence, having both morphologies or
dimorphic).
 Poorly or sharply marginated plaques with punched
out or Swiss cheese sharply marginated areas of
normal skin in the interior of the plaque are also
characteristic, and can be viewed as a variant of the
classic dimorphic lesion.
Annular lesions with sharply marginated exterior and
interior borders are not uncommon. When they
occur, lepromatous-like, poorly defined papules and
nodules may be numerous, but are usually
accompanied by some sharply marginated lesions
somewhere.
 LEPROMATOUS LEPROSY
In lepromatous leprosy (LL) disease, the lack of cell-mediated
immunity toward M. leprae permits unrestricted bacillary
replication and widely disseminated, multiorgan disease.
Poorly defined, skin-colored nodules are the most
characteristic lesions, usually up to 2 cm in diameter, and
symmetrically distributed.
Dermatofibroma-like or histiocytoma-like lesions, usually
multiple, are sharply marginated erythematous papules,
sometimes confluent into plaques, and are not rare in
untreated Mexican-born patients, but are also seen in
Filipinos and Samoans.
 Diffuse dermal infiltration is always present
subclinically and may be overtly manifested by
widening of the nasal root and fusiform swelling of
the fingers, mimicking a rheumatic illness.
With progressive bacillary proliferation, further
cellular infiltration, and the consequent thickening of
the dermis, the skin is thrown into folds producing
the leonine faces often in conjunction with nodular
lesions.
 Less-common presenting skin lesions include
digitate, barely indurated patches of erythema, which
in light-skinned patients are sometimes followed by a
mild hyperpigmentation; in dark-skinned patients,
multiple hypopigmented macules may originate in
such lesions, a veil of melanin concealing the
erythema.
A clinical clue of LLs is a sharply marginated region
in a lesion, perhaps the residual of a BL lesion in a
patient who has downgraded to LLs.
 Hair loss, common on the eyebrows, where it progresses laterally to
medially, but also on the eyelashes and extremities, may be partially
reversible if treated early. Scalp involvement is rare.
Loss of eccrine sweating from sympathetic nerve involvement is common
but rarely so extensive as to lead to heat intolerance. Any given skin lesion
may or may not be hypesthetic but generally, in each patient, some are.
Nerve trunk palsies occur, but are less common than in BL.
Acral distal symmetric anesthesia is to be expected and may be so severe
as to lead to debilitating trophic changes of the hands or feet.
Untreated LL disease is relentlessly progressive, but this course may be
altered by reactional states. LLs and LLp subjects frequently develop ENL,
but LLp patients do not develop reversal reactions (see below), whereas
LLs patients may.
 Systemic Associations

Because of motor or sensory changes in cranial nerve V, the

eye may be at risk in TT and BT disease, as well as in BB,
BL, and LL leprosy.
In the latter group, numerous changes in the cornea and
anterior chamber are possible, iritis being a common serious
change, occurring de novo or in association with reactions.
Corneal insensitivity is the common, treatable change.
Routine ophthalmologic examination is recommended for all
patients.
 In all LL patients and in BL with extensive disease, wide
dissemination of the infection is the rule, but, with the
exception of the upper respiratory tract (tip of the nose
through the vocal cords with rhinitis, septal perforation, and
nasal collapse being not uncommon), eyes and testicles
(atrophy, impotence, and infertility), clinically troublesome
injury is unusual.
With effective chemotherapy, chronic disability from ocular or
upper respiratory tract involvement is less common than
previously, but has not disappeared, making
ophthalmologists and otolaryngologists still vital to the
successful management of patients with leprosy, to evaluate
and treat acute changes, and to prevent chronic changes.
 PREGNANCY AND POSTPARTUM
Pregnancy is a precipitating factor for leprosy in 10 to 25 percent of
women patients, presumably because of altered immunity. When
pregnant, LL and BL patients are predisposed to develop ENL, but in the
postpartum period, they are predisposed to develop reversal reactions,
putatively due to reduced immunity in the former and restored immunity in
the latter.
Of the drugs used to treat leprosy, none have been proven to be safe for
the fetus and one is clearly contraindicated. Fetal damage attributable to
dapsone evidently has not been observed, hence continuation of dapsone
in multibacillary patients is usually recommended. The wishes of the
patient should be carefully considered. Untreated, lactating BL and LL
patients have viable bacilli in their milk, but no definable risk has been
identified in infants ingesting such bacilli.
Dapsone in mother's milk may produce hemolysis in baby.
 INDETERMINATE LEPROSY
Indeterminate leprosy is a term with nearly as many meanings
as it has users. We prefer the definition of Khanolkar,
designating an early lesion, appearing before the host makes
a definitive immunologic commitment to cure or to an overt
granulomatous response.
Clinically, the indeterminate lesion is a hypopigmented
macule, with or without a sensory deficit and acid-fast bacilli,
if found, are in very small numbers. Such lesions are rare in
our clinic.
The term is inappropriately used to describe lesions rich in
bacilli but having neither typical tuberculoid or lepromatous
histological responses, such patients usually being BL and
occasionally LL.
 ACQUIRED IMMUNODEFICIENCY
SYNDROME OR HIV INFECTION

In contrast to the high incidence of tuberculosis and

M. avium-intracellulare infections in AIDS or HIV
patients, leprosy does not behave as an
opportunistic infection in these individuals.
Also, AIDS or HIV does not appear to influence
disease expression (tuberculoid versus lepromatous)
or the frequency of reactional states, but may be a
risk factor for recurrent reversal reactions.
 DISABILITY OF HANDS AND FEET
Approximately one-quarter to one-third of newly diagnosed patients with
leprosy will eventually have some chronic disability secondary to
irreversible nerve injury, usually of the hands or feet, or from eye
involvement.
Weakness from loss of innervation of muscles is a self-evident cause of
disability. Loss of protective sensation is less obvious, but no less real.
When a sharp or hot object cannot be perceived as such, injury occurs.
Because this injury is more severe than if sensation were normal, infection
is more apt to occur. Because the infection can produce no painful signal,
the part is not rested, allowing the infection to become extensive before
help is sought.
Repetitive cycles of injury and infection, permitted by loss of protective
pain sensation, is the source of severe tissue destruction in leprosy.
Management and prevention of the problems arising from nerve injury
require the skills of orthopedic surgeons, podiatrists, plastic surgeons,
physical therapists, orthotists and occupational therapists.
 RELAPSING LEPROSY

Multibacillary patients who are noncompliant or

who develop drug resistance are prone to relapse.
Such individuals present in several ways, including
(1) a reprise of their initial presentation,
(2)florid dermatofibroma-like lesions (histoid lesions),
(3) a reactional state, and
(4) a clinical state of higher resistance than their
initial presentation, for example, an initially LLs
individual having BL or even BT disease.
 Reactional States
Generically, the reactional states of leprosy are distinctive,
tissue destructive, inflammatory processes, putatively
immunologically driven, that greatly increase the morbidity of
the disease and, because of the experience required for
optimal patient care, justify leprology as a clinical
subspecialty.
When present, a reactional state is superimposed upon the
underlying granuloma, but it usually dominates the clinical
picture.
Analogous to the p electron in photobiology, when the
granulomas accept immunologically driven energy, the
excited granuloma is able to injure tissues in ways that it
cannot when in its ground state.
 DELAYED-TYPE HYPERSENSITIVITY
REACTION (JOPLING'S TYPE I REACTION)

Although widely regarded as a DTH response, the

nomenclature is not uniform.
Reversal reaction,= upgrading, has come to be used as
identical to type I, probably because most type I reactions are
associated with reversal.
Designation by mechanism as a DTH reaction is a rational
and acceptable name. DTH reactions are particularly common
in BL patients, but are not rare in LLs, BB, or BT.
Patients may upgrade to a more-resistant granulomatous
posture, remain unchanged, or downgrade to a less-resistant
disease state.
 Clinically, DTH reactions are characterized by the
abrupt conversion of previously torpid plaques to
tumid lesions, and new tumid lesions arising in
clinically normal skin with or without an abrupt onset
of neuritis. A purplish color is characteristic, and even
if not obvious, the dusky erythema may have a
purplish cast.
Iritis and lymphedema (elephantiasis graecorum)
may be concomitant changes. Lesions are rarely
solitary, as can happen in BT upgrading to TT, often
multiple, and occasionally myriad, as in BL or LLs
upgrading to BT.
 Neuritis also ranges from mild to severe, potentially
disastrous, particularly if involving multiple nerves.
DTH reactions may often be a mode of presentation,
and DTH reactions occurring soon after presentation
and the institution of treatment may well have been
DTH reactions from the beginning.
Most common in the first year of treatment, DTH
reactions may occur up to 7 years after starting
therapy, well after treatment has stopped. The
diagnosis of a DTH reaction is primarily clinical, but
histologic confirmation should be sought.
 ERYTHEMA NODOSUM LEPROSUM
(JOPLING'S TYPE II REACTION

ENL (first described by Murata in 1912) occurs most

often in LL, in up to 75 % of cases, but is not rare in
BL patients.
(ENL is not erythema nodosum occurring in leprosy;
it is a leprosy-specific response, which has some
features in common with erythema nodosum.)
It may occur before, during, or after chemotherapy.
The median time of onset is close to 1 year after
onset of treatment.
 Clinically, this reaction is characterized by crops of painful and tender,
bright pink, dermal and subcutaneous nodules arising in clinically normal
skin, in association with fever, anorexia, and malaise.
Of the other organs involved, arthralgias and arthritis are more common in
ENL than are neuritis, adenitis, orchitis/epididymitis, or iritis, but each may
rarely be the initial structure affected. Involvement of both upper and lower
extremities is the rule and facial lesions occur in one-half of the patients. A
neutrophilic leukocytosis is often present, occasionally leukemoid in
degree.
Severe episodes can be associated with an abrupt fall in hematocrit, up to
5 g/dL, easily mistaken for dapsone-induced hemolysis. The response to
thalidomide is dramatic in greater than 90 percent of patients, perhaps
qualifying as a diagnostic criterion.
When ENL is the presenting mode of leprosy, there may be little or no
stigmata of the underlying multibacillary disease. ENL may be precipitated
by pregnancy or pyogenic infections.
 Although episodes of ENL may be occasional or sporadic, in the more
severely involved patients, episodes can be frequent to virtually
unremitting. In the latter, brawny induration of the anterior thighs and
preaxial portion of the arms is characteristic, perhaps a reversible fibrosis.
Other cutaneous variants are annular lesions mimicking erythema
multiforme, vesicles or pseudovesicles in association with papillary
edema, necrotic lesions, ulcers, frank subcutaneous abscesses, and
pustular lesions mimicking pyodermas.
The course of ENL, treated or untreated, ranges from sporadic and
ephemeral, to frequent and persistent, lasting a matter of years. A severe,
difficult to manage, form of ENL is a serious problem in Brazil and other
parts of South America.
The diagnosis of ENL, if considered, is usually not difficult, the clinical and
histologic features being characteristic and the response to thalidomide
often dramatic.
 THE LUCIO REACTION
Clinically, the Lucio reaction, first described by Raphael Lucio in 1853,
consists of hemorrhagic infarcts. Particularly prevalent in Mexico and the
Caribbean region, it is restricted to patients with Latapi's lepromatosis,
described by Fernando Latapi in 1941, a distinctive form of diffuse
nonnodular lepromatous leprosy.
When fully developed, Latipi's lepromatosis manifests a widening of the
nasal root and fusiform enlargement of the fingers, both the consequence
of diffuse dermal infiltration, as well as, a purplish suffusion of the hands
and feet, numerous telangiectatic mats or eruptive telangiectasias, nasal
septum perforation, total alopecia of eye brows and eye lashes, and a
well-developed acral distal symmetric anesthesia.
Firm subcutaneous nodules are palpable but not visible. Ocular sparing is
the rule.
 The Lucio reaction occurs after Latapi's lepromatosis is well
developed but before treatment is initiated. The necrotic
lesions, arising in crops, have the serrated margins
characteristic of septic infarcts and are painful but not tender.
Lesions usually crust and heal with scaring. Ulceration is
common, especially below the knees. Lesions vary in size and
extent, ranging from a few small lesions on the ankles to
many large lesions, placing life in peril.
With dapsone alone, lesions may worsen, but in our
experiences, new lesions cease within 1 week of beginning
rifampin, suggesting a strict requirement for viable bacilli.
 LABORATORY FINDINGS

Most laboratory changes occur in LL or extensive BL

disease. Hyperglobulinemia is the most common,
giving an elevated sedimentation rate. A biologic
false-positive serologic test for syphilis, anemia of
chronic disease, and mild lymphopenia are also
common.
Clinically insignificant antiphospholipid antibodies are
present in 50 % of LL patients, and may give rise to a
lupus anticoagulant or agglutination of sheep
erythrocytes (Rubino factor). If sought, the stained
smear of the buffy coat shows bacilli up to 10 5/mL.
 Elevated serum lysozyme and angiotensin-
converting enzyme values reflect the extensive
accumulation and activation of macrophages
synthesizing these proteases.
Proteinuria, not uncommon, is associated with a
focal glomerulonephritis, seen mostly in patients
with ENL. As manifested by high serum follicle-
stimulating hormone (FSH) and luteinizing hormone
(LH) values, but low testosterone levels, LL disease
involves the testicles in a majority of men with LL,
but in a minority of men with BL.
 PATHOLOGY
Microscopic Changes

Granulomatous responses are the common tissue

reactions in leprosy, with epithelioid differentiation of
macrophages being characteristic of TT, BT, and BB,
and undifferentiated or foamy macrophages being
the hallmark of BL, LLs, and LLp.
 Exceptions can occur, include
(1) chronic inflammation, particularly in BL and
indeterminate disease,
(2) lobular panniculitis in ENL, and
(3) vasculitis in ENL and the palpable-only nodules of
Latapi's lepromatosis. At the level of the low-power
objective, a patchy infiltrate throughout the dermis, or
a bizarre sausage-shaped infiltrate (following
neurovascular bundles) should include consideration
of leprosy in the differential diagnosis.
 SPECTRAL GRANULOMATOUS
PATTERNS

In de novo TT lesions, small, well-developed epithelioid

tubercles are surrounded by large lymphocytic mantles.
In TT upgrading from BT, abundant Langhans-type giant cells
and a brisk exocytosis into the epidermis are added to the
preceding pattern, and caseation may be present.
In BT tissues, lymphocytic mantles are less well developed,
Langhans-type giant cells are inconstant, and, if present at all,
epidermal exocytosis is focal.
 Acid-fast bacilli are not found in TT and are only
rarely seen in BT. The presence of bacilli or plasma
cells in what otherwise appears to be BT warrants
consideration of a reversal reaction.
In BB, lesions are lymphopenic, giant cells are
absent, and bacilli are common.
The classic BL tissue responses are a moderately
dense lymphocytic infiltrate restricted to the space
occupied by the macrophages, and lamination of the
perineurium with infiltrating inflammatory cells.
 A chronic lymphohistiocytic infiltrate is an alternate pattern.
In LLs, lymphocytes are present focally or sparsely distributed
generally, and the laminated perineurium is not infiltrated.
In LLp, lymphocytes are fewer than in LLs, and there is no
perineural lamination.
From BL to LLp, the extent of the granuloma and the numbers
of globi (large secondary lysosomes packed with bacilli) are
highly variable, but bacilli are always easily found, even if with
great quantitative differences.
 PATTERNS IN REACTIONAL
STATES
Reversal reactions, when compared with prereactional
tissues, occasionally do not differ, but may show edema,
epithelioid change, increased lymphocytes, Langhans-type
and foreign-body giant cells, epidermal thickening, and,
occasionally, enhanced bacteriolysis.
ENL lesions usually have neutrophils, a marked increase in
lymphocytes, epidermal thickening, and a gradient of
inflammatory cells, scant in the papillae and heavy in the deep
dermis or subcutis.
Lucio lesions feature ischemic necrosis in both epidermis and
dermis, vessel occlusion by thrombosis or endothelial
proliferation, and heavy bacillary parasitization of endothelial
cells.
 Immunopathology and Immunology

Investigation into the immunology offers 3 promises:

(1) a better understanding of the disease itself; in
particular, the immunopathogenesis of the
granulomatous spectrum and the reactional states;
(2)eradication or control of the disease by
vaccination; and
(3) development of a probe of CMI in humans that,
when understood in the model of leprosy, will
illuminate other disease processes.
 CELLULAR IMMUNITY
Diversity of leprosy is two polar forms. The high-resistance
tuberculoid form is characterized by few lesions, rare
organisms, epithelioid cell granulomas, and a tendency to
self-cure. A sharp margin on a plaque is the inscription of
anti- M. leprae DTH on the skin; a nerve trunk palsy is its
inscription on a peripheral nerve.
Tuberculoid leprosy appears to be an entirely different
disease than the low-resistance lepromatous form,
characterized by wide dissemination, abundant organisms,
foamy macrophages, and, if untreated, relentless
progression. Strain variation of M. leprae is an unlikely
explanation for the diverse host responses in leprosy.
 The observations of a positive lepromin skin test in tuberculoid
subjects and unresponsiveness in lepromatous patients was
the first objective and reproducible evidence that host immunity
was the mechanism of polar diversity.
Lymphocyte transformation tests provided an in vitro correlate
of the lepromin skin and substantial evidence that mediation of
polar diversity was through the cellular-immune response. On
the contrary, antibody responses to M. leprae were found to be
stronger in lepromatous patients, indicating the humoral
immunity does not lead to resistance to disease.
 Immunophenotypic studies established an important difference between
the lymphocyte subsets infiltrating skin lesions and tuberculoid subjects
having a predominance of the CD4 subset (CD4:CD8 = 2:1), but
lepromatous patients having a predominance of the CD8 subset
(CD4:CD8 = 1:2).
The skewing of T cell subsets in lesions was independent of those in the
peripheral blood, because all patients had a normal CD4:CD8 ratio of 2:1.
Therefore, it is important to study the immune response of patients at the
site of disease activity, that is, the skin lesions. By using the sequential
application of reverse transcriptase and polymerase chain reaction
techniques to tissue extracts, studies of mRNA cytokine profiles in polar
tissues have provided a functional explanation for their
immunopathogenesis.
 Tuberculoid lesions have a type 1 (TH1 or TH1-like)
proinflammatory profile, in particular abundant mRNA
coding for interleukin (IL)-2, interferon (IFN)-, and IL-
12, but scant mRNA coding for IL-4 or IL-10. In
contrast, lepromatous tissues have a type 2 (T H2 or T
H2-like) anti-inflammatory profile, in particular,
abundant IL-4 mRNA and IL-10 mRNA, but little
mRNA coding for the type 1 cytokines.
Furthermore, CD4+ T cells in tuberculoid lesions were
shown to produce IFN-, whereas, CD8 T cells in
lepromatous lesions accounted for the production of
IL-4. The presence of type 1 cytokines likely results in
strong T cell and macrophage activation, the result
being cell-mediated immunity to localize the infection.
 On the other hand, the type 2 cytokines found in
lepromatous lesions likely lead to the strong antibody
responses, but concomitantly inhibit T cell and
macrophage responses resulting in progression of
the infection.
The importance of this paradigm is reflected in
experiments designed to augment cell-mediated
immunity in lepromatous patients, where the
administration of recombinant IFN- to lepromatous
patients reduced the number of bacilli infiltrating
tissues.
 The decision by the host as to which cytokine profile
to make, that is, type 1 or type 2, may rest with the
response of the native immune system to M. leprae.
Cytokines produced by the native immune system
may profoundly affect the adoptive response, and
some of the Toll-like receptors (TLR) of the native
system are triggered by mycobacterial lipoproteins.
 Reversal reactions and positive lepromin skin tests
(Mitsuda reactions), long considered to be delayed-
type hypersensitivity responses, also have a CD4+ T
cell predominance and a type 1 cytokine profile, but
both differ from tuberculoid lesions by having a
relative excess of M. leprae-reactive T cells, perhaps
related to these being recent lesions.
Host cytokine profiles are subject to change. LLs
patients undergoing a reversal reaction switch from a
type 2 to a type 1 profile; the mechanism of the
switching is yet to be determined.
 ANTIBODY IMMUNITY ENL

Regarded to be mediated by immune complexes.

There are large amounts of anti- M. leprae
antibodies in both LL and BL patients.
All classes of antibodies are represented and their
specificities directed against a number of substrates
including specific and cross-reacting peptides, but
these antibodies do not confer disease protection.
 Also, the blood of BL and LL patients contains abundant
antigens including intact bacilli, up to 10 5/mL. Therefore, it is
readily conceivable that BL and LL patients should be subject
to immune complex-mediated tissue injury. The best direct
support for the hypothesis that ENL is immune complex
mediated is the presence of split complement products in
serum, which is consistent with extravascular complement
activation within tissues.
Inferential evidence is that of neutrophil infiltration, suggesting
an Arthus phenomenon, and an excess of glomerulonephritis
in ENL patients. Also, the cytokine profile in ENL is type 2,
despite a preponderance of the CD4+ subset.
 However, evidence for immune complex mediation is far from
persuasiveit has not been reproduced and it is confounded
by a number of observations, including human leukocyte
antigen (HLA)-DR framework antigen in lesional epidermis, an
increase in IFN- containing cells by hybridization studies, an
excess of IL-2staining cells as compared with LL tissue, and
the precipitation of ENL by the administration of rIFN- .
Also, other thalidomide responsive syndromes, such as
rheumatoid arthritis, tuberculosis cachexia, multiple myeloma,
and Behet's syndrome, are not directly immune complex
mediated. Perhaps both immune complexes and cellular
immunity are important in the pathogenesis of ENL.
 Littleis known concerning the immunopathogenesis
of the Lucio reaction.
The abundant acid-fast bacilli in endothelial cells
could be the optimum location for presentation of
antigen to antibody.
Also, the cryoprecipitate from Lucio serum is more
indicative of complement activation than that from
ENL patients.
 DIAGNOSIS

A firm diagnosis of leprosy requires the satisfaction

of one of two criteria:
1. a consistent peripheral nerve abnormality
2. the demonstration of mycobacteria in tissues.
 The diagnosis begins with a suspicion of leprosy,
several known risk factors, including
(1) birth or residence in an endemic area, which is
almost sine qua non for the diagnosis,
(2) a blood relative with the disease, which could
reflect transmission, common genetic makeup, or
common environmental exposure, and
(3) armadillo (seven-banded) exposure in North
American.
 Possibility of leprosy
The possibility of leprosy also should be suggested by
particular clinical constellations such as
(1) simultaneous skin lesions and peripheral nerve
abnormalities,
(2) a differential diagnosis that includes granuloma, vasculitis,
or lymphoma,
(3) a peripheral neuropathy of unknown type in a patient in or
from an endemic area, the so called pure neuritic leprosy, and
(4) simultaneous palsies of cranial nerves V and VII,
considered to be leprosy until proven otherwise.
 Because M. leprae does not grow in cell-free media,
demonstration of mycobacteria by their acid-fast property is
used most commonly in diagnosis. Acid-fast bacilli in tissue
sections are best shown by carbolfuchsin staining, using
modifications of the Ziehl-Neelson method, collectively called
Fite-Farraco stains.
M. leprae, like Nocardia species, is only weakly acid-fast. In
smears, either the Ziehl-Neelson method or oramine-rhodamine
staining with fluorescent microscopy is satisfactory.
Because of characteristic clinical and histologic changes,
positive specification of M. leprae is rarely required.
 Characteristic histologic changes are extremely
helpful in suggesting or corroborating a diagnosis of
leprosy, but, excepting the presence of epithelioid
cell granulomas within nerves, are not absolutely
diagnostic.
 False Negatives
The six errors that lead to missing the diagnosis of leprosy are
(1)failure to consider the diagnosis, usually from ignoring birth or residence
in an endemic area;
(2) failure to inform the pathologist of the suspicion of leprosyan infiltrate
may not be granulomatous, thus no acid-fast bacilli stain will be done by
the pathologist if there is no known clinical suspicion;
(3) an inadequate neurologic exam, in particular, the patient is not properly
instructed to distinguish between dull and sharp (if the patient is not
instructable, absence of a histamine-induced axon reflex flare, with a
positive symmetric control, is good evidence of type C pain fiber loss);
(4) presence of pinprick perception does not exclude loss of heat and cold
discrimination;
(5) improper staining for bacilli in biopsy specimensin a conventional
Ziehl-Neelson stain M. leprae, being only weakly acid-fast, may be
decolorized altogether; and
(6) tissue sampling errorthe advancing border should be selected for
biopsy not the clearing center.
 False Positives

The four errors that lead to improperly diagnosing leprosy are

(1) inflammatory lesions may have blunted pain perception
(histamine tachyphylaxis), producing diminished sensation
similar to that seen in some leprosy lesions;
(2) atypical mycobacterial infection may have the abundant acid-
fast bacilli characteristic of lepromatous disease;
(3) environmental mycobacteria-like water, including that used to
process tissue sections, as suggested by bacilli in the
embedding medium, or not associated with cellular infiltrates;
(4) from time-to-time, cunning artifacts are misinterpreted as
acid-fast bacilli. If a patient, suspected of having leprosy, has
no history of residence in a known endemic area, then one of
these errors should be seriously considered.
 ALTERNATIVE METHODS
Alternative methods of establishing a diagnosis have been pursued but,
at present, are of limited value. M. leprae specific antibodies are most
prevalent in multibacillary cases, where there is no need for better
diagnosis, and are, in endemic areas, far more prevalent than the
disease, thus further restricting their utility.
Polymerase chain reaction (PCR) may be negative in up to one-half of
paucibacillary cases, making a positive signal of value but a negative
signal of no help. PCR should be most helpful in the diagnosis of patients
with lesions having acid-fast bacillus, but no stigmata of leprosy, and
negative cultures.
Lepromin skin testing, because of the high rate of positive reactions in
unexposed adults, is not useful in diagnosis, but can be of value in
classification of diagnosed patients; all TT and most BT (85 percent in
our experience) being positive (3 mm or more of induration at 21 days)
and BB through LLp being negative (less than 3 mm).
 TREATMENT

For paucibacillary (TT or BT) the WHO recommends

the combination of unsupervised dapsone
(bacteriostatic) 100 mg daily and supervised rifampin
(bactericidal) 600 mg monthly for a duration of 6
months.
We prefer dapsone 100 mg daily for 2 to 3 years,
with or without rifampin 600 mg monthly, with follow-
up examination at 1 and 2 years after discontinuing
treatment.
 Multibacillary
For multibacillary (BB, BL, and LL) the WHO recommends unsupervised
dapsone 100 mg daily, supervised rifampin 600 mg monthly and
clofazimine 50 mg daily, unsupervised, and 300 mg monthly supervised
for a routine duration of 2 years.
The rationale for this regimen is that rifampin will kill all susceptible
organisms, including those resistant to dapsone, and dapsone will
eventually eliminate all susceptibles, including those resistant to rifampin;
clofazimine is added to obviate the risk of primary dapsone resistance.
This regimen is considered by the WHO to be curative and is the
cornerstone of the anticipated reduction of the prevalence of leprosy to
less than 1 case per 10,000 people.
The report of a 20 percent relapse rate within 8 years after completion of
this regimen suggests a need for alternative approaches, particularly in
heavily bacillary patients (biopsy index of 5 or more).
 Other regimens
Because the incidence of primary dapsone resistance is low
in our patient population, we often use the combination of
rifampin 600 mg daily and dapsone 100 mg daily for 3 years
followed by dapsone 100 mg daily indefinitely or cessation of
treatment.
Alternative regimens of rifampin 600 mg daily in combination
with either minocycline (bactericidal) 100 mg daily or
clarithromycin (bactericidal) 500 mg daily for 2 to 3 years,
followed by monotherapy, has been well tolerated, except for
hyperpigmentation from the minocycline.
Short-term therapy with three microbicidal agents (rifampin,
minocycline, and ofloxacin or moxifloxacin) is currently
experimental.
 Reversal reactions
In reversal reactions, because of the risk of permanent nerve
damage, prompt institution of prednisone therapy (0.5 to 1
mg/kg per day) is recommended (but still wanting a controlled
trial). The dose of prednisone is titrated against overt nerve
tenderness, the patient's symptoms, and careful sensory
evaluation of hands and feet, for example with graded
Weinstein filaments.
Once instituted, therapy should be tapered slowly and
continued for a minimum of 6 months. If response of neuritis
to prednisone is not prompt, then rest, enforced with splinting
of effected extremities, is also recommended.
 Thalidomide In ENL
In ENL, thalidomide use is dramatically effective in a majority
of patients, if not interdicted by its teratogenic effects.
For outpatients, we usually start with 100 to 200 mg nightly of
thalidomide and, if it is only partially effective, we add
prednisone in a 0.5 to 1.0 mg/kg range, tapering the
prednisone over the subsequent 6 to 8 weeks.
Higher doses of thalidomide are usually restricted to
inpatients in whom excessive sleepiness is not a problem. If
not available, corticosteroids in conjunction with clofazimine at
200 mg per day may be effective.
Thalidomide is slowly tapered to 100 mg and then to 50 mg
daily.
 Dapsone

Adverse reactions: the dapsone syndrome, a rare,

potentially fatal infectious mononucleosis-like
condition and three kinds of hemolytic anemia,
almost universally from a direct membrane effect,
uncommonly from a glucose-6-phosphate deficiency,
and rarely from an idiosyncratic response.
In the long-term: peripheral neuropathy, usually
motor with a sensory component, and, rarely, bone
marrow suppression, especially agranulocytosis.
 Rifampin
The serious problem with rifampin is hepatotoxicity.
Red urine is alarming but banal.
As a P450 inducer, rifampin may lessen the effect of
other drugs, for example, oral contraceptives
resulting in pregnancy, or reduced anti-inflammatory
activity of corticosteroids.
Once monthly use is rarely associated with severe
hemolysis and acute renal failure.
 Clofazimine

Clofazimine produces skin darkening from the

clofazimine itself in the near-term and from a ceroid-
lipofuscin pigment in the long-term.
At usual doses of 50 to 100 mg a day, gastrointestinal
intolerance, dry skin, and acquired ichthyosis are
common.
Prolonged administration of large doses may produce
a novel enteropathy secondary to mucosal and
enteric lymph node drug accumulation. Accumulation
in the spleen may predispose to rupture.
 Thalidomide

Thalidomide, infamous for teratogenicity, may

produce constipation and dizziness.
Neuritis, a common side effect in nonleprosy
patients, appears to be rare in ENL patients.
 Minocycline

Long-term use of minocycline may be limited by

hyperpigmentation, much more common in leprosy
than in acne, perhaps related to the large
accumulation of macrophages in leprosy.
We have seen both diffuse hyperpigmentation and
intense hyperpigmentation at the site of lesions,
usually on the legs or feet.