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.

Multiple flesh to yellowish colored nodules with numbness  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  Fallen dramatically in the past decade.  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 disease is common. lepromatous patients.  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.

 Possibility of Leprosy:  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  BT (borderline tuberculoid)  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.

(Jopling’s type 1 reaction)  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  ENL occurs most commonly in LL, less in BL.  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  Occur exclusively in diffuse lepromatous leprosy.  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  WHO: the combination of dapsone (bacteriostatic)  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  Fitzpatrick: rifampin 600mg QD, dapsone 100mg QD  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  Thalidomide is dramatically effective in a majority of  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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