Lepromatous Leprosy

高雄榮總 皮膚科 賴名耀 宗天一

Case Report Present Illness A 33 year-old Thai male suffered from yellowish to flesh-color skin eruption with numbness and loss of light touch sensation over face, trunk and 4 limbs for about 3 months. Throughout the whole course of disease, There was no fever, no chills, and no lymphadenopathy.

Past History Denied any systemic disease. Family History Non-contributory.

Clinical Finding: Multiple flesh to yellowish colored nodules with numbness and loss of light touch sensation over face, trunk and 4 limbs. Pathological Findings: Several granulomas with foamy histiocytes in the dermis. Acid -fast stain: (+), Ziehl-Neelsen stain: (+), Fite-Farraco stain(+). Inflammation involves the small nerve trunks confirmed by S-100 staining. Diagnosis: Lepromatous leprosy Management: He was sent back to Thailand.

Discussion

Leprosy

Epidermiology It is primarily a disease of developing countries

Prevalence: Fallen dramatically in the past decade. Incidence (1992, WHO): 690,000 new cases per year. Subclinical infection is common in endemic areas.

The route of infection: Human to human, favor respiratory transmission.

Armadillo and sphagnum moss: non-human sources.

Epidermiology MHC class II antigens: influence disease expression.

Lepromatous leprosy--- M : F = 2 : 1

The tuberculoid form being dominant wherever the disease is common.

The median age of onset is less in tuberculoid than in lepromatous patients.

Leprosy is predominantly a young person’s disease (median age of onset is < 35 years of age)

Required for transmission: prolonged close contact.

Incubation time of tuberculoid leprosy: up to 5 years; lepromatous leprosy: 20 years or longer.

Risk Factors: Birth or residence in an endemic area

A blood relative with the disease

Armadillo (nine-banded) exposure in North Americans.

Possibility of Leprosy: Simultaneous skin lesions and peripheral nerve abnormalities Differential diagnosis includes granuloma, vasculitis or lymphoma. A peripheral neuropathy of unknown type in a patient in or from an endemic area, (so-called pure neuritic leprosy) Simultaneous palsies of cranial nerves V and VII, considered to leprosy until proven otherwise.

Criteria for Diagnosis The presence of a consistent peripheral nerve abnormality or the demonstration of mycobacteria in tissues. Several kinds of peripheral nerve abnormalities in leprosy: Nerve enlargement (usually perceived as asymmetry). Sensory loss in skin lesions. Nerve trunk palsies (usually with both sensory and motor loss). Acral distal symmetric anesthesia (type C fiber). Anhidrosis: sympathetic nerve involvement. Uncommon peripheral nerve abnormalities: Nerve abscesses (palisading granulomas formed about cutaneous sensory nerves) The carpal tunnel syndrome.

Identification and Quantitation of Bacilli Acid-fast stain: weak.

Modifications of the Ziehl-Neelsen method

(collectively called Fite-Farraco stains)

Bacilli are usually found in macrophage and nerves.

Bacillary index (BI): the numbers of bacilli per oil-

immersion field (OIF) or OIFs sought to find one

bacillus

Other Methods of Diagnosis Antibodies directly against phenolic glycolipid I or

lipoarabinomannan.

Polymerase chain reaction (PCR).

Classification The dichotomy: multibacillary or paucibacillary The Ridley system: TT (polar tuberculoid) BT (borderline tuberculoid) BB (borderline/midborderline) BL (borderline lepromatous) LLs (subpolar lepromatous) LLp (polar lepromatous) The paucibacillary: TT and most BT. The multibacillary: BB, BL, LLs and LLp. Lepromin skin test: classification of diagnosed patients Positive: all TT and most BT. Negative: others.

Clinical Pathology of Leprosy Early, Indeterminate Leprosy Slight pandermal perineurovascular and peri- appendageal chronic inflammation. Without demonstrating bacilli: Diagnosis can only be presumptive Lepromatous leprosy (LL) The lesions usually are numerous and symmetrically arranged. Three clinical types: macular, infiltrative-nodular and diffuse. A distinctive variant of LL: histoid type.

Clinical Pathology of Leprosy Lepromatous leprosy -- Infiltrative-nodular type The classical and most common variety. The patients are not notably hypoesthetic disturbances of sensation and nerve paralyses develop after large peripheral nerve involved. Most common involved nerve: ulnar, radial and common peroneal nerves. Extensive cellular infiltrate with separated from the epidermis by a narrow grenz zone of normal collagen. The macrophages have abundant eosinophilic cytoplasm and contain mixed solid and fragmented bacilli . Lymphocyte infiltration is not prominent, but there may be many plasma cells

Clinical Pathology of Leprosy Lepromatous leprosy -- Diffuse type (Lucio leprosy): Most common in Mexico and Central America. Diffuse infiltration without nodules. Acral , symmetric anesthesia is generally present. Characteristic heavy bacillation of the small blood vessels in the skin. Lepromatous leprosy -- Histoid type The occurrence of well-demarcated cutaneous and subcutaneous nodules resembling dermatofibromas. It frequently follows incomplete chemotherapy or acquired drug resistance, leading to bacterial relapse.

Clinical Pathology of Leprosy Lepromatous leprosy -- Histoid leprosy

The highest loads of bacilli.

The majority are solid-staining, arranged in clumps

like sheaves of wheat.

Macrophage reaction is unusual.

Macrophages frequently become spindle-shaped

and oriented in a storiform pattern, similar to

fibrohistiocytoma.

Clinical Pathology of Leprosy Lepromatous leprosy -- with antimycobacterial therapy Degenerate bacilli accumulate in the macrophages (the so-called lepra cells or Virchow cells), which have foamy or vacuolated cytoplasm, resembling xanthoma cells Fite stain reveals that the bacilli are fragmented or granular and disposed in large basophilic clumps called globi especially in very chronic lesions. The nerves in the skin may contain considerable numbers of leprosy bacilli, but remain well- preserved for a long time and slowly become fibrotic.

Clinical Pathology of Leprosy

Lepromatous leprosy -- with antimycobacterial therapy

When lepromatous leprosy is treated, the bacterial

debris to be cleared by host macrophages.

The M lepra antigen may persist longer and can be

demonstrated by immunocytochemical stains

(Fite or silver) even when no bacilli are evident.

Clinical Pathology of Leprosy Borderline lepromatous (BL) leprosy Less numerous and less symmetrical than LL lesions. Often display some central dimples. The lymphocytes are more prominent in BL and there is a tendency for some activation of macrophages to form poorly to moderately defined granulomas. Perineural fibroblast proliferation forming an typical “onion skin” in cross section. Midborderline (BB) leprosy The lesions are irregularly dispersed and shaped erythematous plaques with punched-out centers. Dermal edema is prominent in the lesions. Macrophages are activated to epitheloid cells

Clinical Pathology of Leprosy Borderline tuberculoid (BT) leprosy The lesions are asymmetrical and may be scanty. Dry, hairless plaques with central hypopigmentation. Nerve enlargement is usually found and the lesions are usually anesthetic. Granulomas with peripheral lymphocytes follow the neurovascular bundles and infiltrate sweat glands and erector pili muscles. Langhans’ giant cell are variable in number and are not large in size. Typical nerve erosion and obliteration. Granulomas along superficial vascular plexus frequently S-100 stain showed perineural & intraneural granuloma.

Clinical Pathology of Leprosy Tuberculoid (TT) leprosy The lesions are scanty, dry, erythematous, hypo- pigmented papules or plaques with sharply defined edges. Anesthesia is prominent (except on the face). The number of lesions ranges from 1 to 5, and the lesions heal rapidly on chemotherapy. Primary TT leprosy has large epitheloid cells arranged in compact granulomas along with neurovascular bundles with dense peripheral lymphocyte accumulation Langhans’ giant cells are typically absent. Dermal nerve may be absent or surrounded and eroded by dense lymphocyte cuffs. Bacilli are rarely found.

Histopathologic Differential Diagnosis

Tuberculoid leprosy should be D.D. with:

Sarcoidosis, tuberculosis, granuloma annulare

granulomatous leishmaniasis.

Lepromatous leprosy should be D.D. with:

Xanthoma

Other mycobacterioses: M. avium-intracellulare

-- histoid-like multibacillary lesions.

Leprosy Reaction The reactional status of leprosy are distinctive, tissue destructive, inflammatory processes, putatively immuno- logically driven greatly increasing the morbidity of the disease. Delay-Type Hypersensitivity Reaction (Jopling’s type 1 reaction) Type 1 reactions are common in BL patients, but are not rare in LL or BT patients. Reaction induces increased intraneural inflammation and edema, which is damaging. At worst, there is a caseous necrosis of large peripheral nerves resulting from upgrading reactions..

Leprosy Reaction

Delay-Type Hypersensitivity Reaction

Edema within and about the granulomas and prolifer-

ation of fibrocytes in the dermis.

In upgrading reactions, the granuloma becomes more

epitheloid and Langhans’ giant cells are larger.

There may be erosion of granulomas into the lower

epidermis and fibrinoid necrosis with granulomas and

even within dermal nerves.

In downgrading reactions, necrosis is much less

common and the density of bacilli increases.

Leprosy Reaction Type 2 reaction (Erythema nodosum leprosum, ENL) ENL occurs most commonly in LL, less in BL. Tender, red plaques and nodules together with areas of erythema and occasionally also purpura and vesicles. It is accompanied by fever, malaise, arthralgia and leukocytosis. This is the only type of reactional leprosy that responds to treatment with thalidomide. Polymorph neutrophils may be scanty or so abundant as to form a dermal abscess with ulceration Foamy macrophage containing fragmented bacilli or mycobacterial debris. A necrotising vasculitis in some cases of ENL.

Leprosy Reaction Lucio Reaction Occur exclusively in diffuse lepromatous leprosy. It usually occurs in patients who have received either no treatment or inadequate treatment. The lesions consist of barely palpable, hemorrhagic, sharply marginated, irregular plaques. There may be repeated attacks or continuous appearance of new lesions for years. Endothelial proliferation leading to luminal obliteration with thrombosis in the medium-sized vessels of the dermis and subcutis. Dense aggregates of bacilli are found in the walls and the endothelium of vessels.

Treatment Paucibacillary disease (TT or BT) WHO: the combination of dapsone (bacteriostatic) 100mg QD and rifampin (bactericidal) 600mg monthly for a duration of 6 months. Fitzpatrick: dapsone 100mg QD for 3-5 years, with or without rifampin 600mg monthly, and follow-up exam at 1-2 years after discontinuing treatment. Multibacillary disease (BB, BL, and LL) WHO: dapsone 100mg QD, rifampin 600 mg monthly and clofazimine (bacteriostatic) 50mg QD and 300mg monthly for a routine duration of 2 years. 20% relapse rate within 8 years after completion of this regimen.

Treatment Other regimens for multibacillary diseases Fitzpatrick: rifampin 600mg QD, dapsone 100mg QD for 3 years, followed by dapsone 100mg QD indefinitely. minocycline (bactericidal) 100mg QD and rifampin 600mg QD for 2-3 years followed by monotherapy. Others: clarithromycin and fluoroquinolone (bactericidal)

In reversal reaction: Prednisolone therapy (0.5-1.0 mg/kg per day), tapered slowly and continued for a minimum of 6 months.

Treatment In ENL: Thalidomide is dramatically effective in a majority of patients. Thalidomide 100-200 mg QN, may add prednisolone (0.5-1.0 mg/kg), tapering later over 6-8 weeks. Glucocorticoid in conjunction with clofazimine at 200 mg/day may be effective. Thalidomide is slowly tapered to 100mg and then 50mg QD. Adverse reactions of dapsone treatment: Dapsone syndrome, hemolytic anemia, peripheral neuropathy, bone marrow suppression

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