LEPROSYLEPROSY

IntroductionIntroduction

- A chronic granulomatous infection caused by M. leprae

- Nowadays, mostly a disease of developing countries

- A disabling, deforming and stigmatizing disease

- Primarily affects the skin & nerves- When untreated, may result in

characteristic deformities- Early diagnosis & prompt treatment

- In 1873 G.H. Armauer Hansen – identifies M. leprae

- Earliest description - from India

Etiology M. leprae- first

described by Armauer Hansen in 1873

- It is confined to humans, armadillos

- grows best in cooler areas of the body; skin, peripheral nerves, anterior chamber of the eye, testes

- M. leprae - non-cultivable - Gram +ve - non-motile - aerobic - obligate IC acid fast bacilli - Its unique trisaccharide binds to basal lamina of Schwann cells

- Don’t grow on artificial media

- Foot pad of mice, armadillos

- Humans – primary reservoir

- Animal reservoir armadillos monkeys chimpanzee

Epidemiology

- A disease of the developing world- India has 2/3 of the world’s leprosy

burden- M ׃F 2:1/lepromatous/- Predominantly youngs /2nd or 3rd

decade/- Long Incubation period for tuberculoid- up to 5 years for lepromatous – 20 years or longer

- Requirements for the spread of leprosy

• contagious patient • susceptible individual • close or intimate contact

- Contact with a tuberculoid case carries a very low risk

- Transmission – uncertain ○ nasal droplets ○ skin-to-skin contact – not

considered as an important route

-- Goal of WHO- prevalence rate of less than 1 case/10,000 persons

Pathogenesis

- M. leprae- lives within cells /macrophages, Schwann cell/

- Requires a temperature of ~ 35ºC- For disease susceptibility- genetic &

environmental factors- Source of infection- untreated multibacillary pts- Inhaled M. leprae multiply- Has brief bacteremic phase before binding to

macrophages or Schwann cells

- Depending on the specific CMI, disease can progress or resolve spontaneously

- Less than 5% of pts develop the disease- In the majority, the immunological defense kills

all the bacilli- Intracellular pathogen – recognized by the

innate immune system- Macrophage- play an important role- They present the antigen to the T cells- Adequate activation of macrophages is key to

killing the IC bacilli

- Proper recognition of M. leprae by APC

→Activation of Macrophage → phagocytosis of

M. leprae → complete bacillary lysis bacterial

processing proceeds to antigenic peptide

levels

- Presentation of proper, specific & complete

M. leprae antigen → activation of naive T

cells with the generation of IL-12

→ Th1 response → strong CMI

- A predominantly Th1 response is seen in tuberculoid leprosy patient → IL-2, IFN- γ & TNF-β → maintain inflammation

- Th2 response- in lepromatous patient → IL-4, IL-5, IL-10 → suppress macrophage activity

strong humoral response /Ig M/

Classification

- The granulomatous spectrum of disease described by Ridley & Joplin ׃

■ TT /polar tuberculoid/ ■ BT /borderline tubeculoid ■ BB / borderline/ ■ BL / borderline lepromatous/ ■ LLs LLp /subpolar , polar

lepromatous/

- Classification determined by clinical &

histological changes- TT & LLp are stable poles- In all cases of TT & most BT – AFB

cannot be found

- WHO proposed a classification ׃ ● paucibacillary/PB/ ● multibacillary/MB/

- PB leprosy ׃ /TT, IL & smear –ve BT/ ○ few lesions /< 5 / ○ no AFB found - MB leprosy ׃ /smear +ve BT, BB , BL & LL/ ○ multiple / ≥ 5/ ○ one or more AFB

Polar tuberculoid leprosy

- Immunity is strong- Plaque having

annular configuration

- both border is sharply marginated

- Indurated, erythematous, scaly

- solitary

Borderline tuberculoid leprosy

- Immunity is strong to restrain infection

- Somewhat unstable

may have sharply marginated satellite papules

- Lesions larger- Multiple,

asymmetric- Impaired sensation- Nerve trunk

involvement, enlargement or palsies

- Commonly not more than two nerves

Borderline leprosy

- mid-zone of the granulomatous spectrum

- most unstable - patient quickly down regulates or

upregulate - annular lesion - sharply margins- Large plaque with islands of normal

appearing skin- Patient are rarely seen

- Generally, annular & plaque lesion- numerous, asymmetric

- Lepromatous like nodules- if numerous symmetric

- Nerve trunk palsies → motor & sensory deficit

Lepromatous leprosy- Lack of CMI → unrestricted

proliferation & widely disseminated multiorgan disease

- Poorly defined nodules- most common lesion/up to 2cm/

- Symmetrical distribution- Diffuse dermal infiltration

Indeterminate leprosy

- An early lesion appearing before the host makes a commitment to cure or to an overt granulomatous response

- Hypopigmented macule or patch - Associated sensory deficit may or

may not be present- AFB almost always negative ,- Have neither typical tuberculoid or

lepromatous histological patterns- More than 75% will heal

spontaneously

Pure neural leprosy

- Involve only the nerves without skin changes

- Sensory, motor deficit- Thickened nerve with or without

nerve damage- Skin smears are negative- As PB if only one nerve & nerve

biopsy smear is –ve- As MB if ≥ 2 nerves & nerve biopsy

smear is +ve

Clinical findingsHistory- Risk for those born or resident in endemic area- Duration of symptoms, history of previous Rx- Peripheral neuropathy, nasal stuffiness, ocular

symptoms

- 90% Hx of numbness first→ sometimes years before the skin lesions appear

/Temp. → light touch → pain → deep pressure/

- Especially apparent in hands & feet

- complaint of burn or an ulcer

Examination ׃• Cutaneous lesions - character, number & distribution - Hypopigmented macule, plaque - may or may not be hypoesthetic • Neuropathies - assess for hypoesthesia /light

touch, pinprick/ anhidrosis -ulnar, peroneal N, median, radial

cutaneous N, post tibial N - enlargement , tenderness

Palpating the nerves: - enlargement /tenderness - use 2 or 3 fingers - should be rolled over the surface of the underlying bone

• Eye involvement ▫ Lagophthalmos - inability to close

the eye - from involvement

of the facial N ▫ Decreased corneal

reflex - ophthalmic branch

of trigeminal N - dry eyeCorneal ulceration,

scarring, blindness

Extraoccular

Madarosis- Loss of hair eye

brow

Leonine facies- The skin is

thrown into folds

Examination of the hands & feet

Look for ○ skin cracks, wounds ○ clawed

fingers & toes ○ foot drop ○ wrist drop ○ shortening

& scarring of fingers &

toes

Peripheral nerve change ׃

1- Nerve enlargement2- Sensory impairment3- Nerve trunk palsies4- Stocking- glove pattern of

sensory impairment5- Anhidrosis

Nerve damage ׃ ☻anesthesia ☻muscular weakness ☻contracture ☻autonomic dysfunctionThese results in ׃ Trauma, bruising, burn, tissue

necrosis ulceration, cellulitis, osteomyelitis

& loss of tissue

Diagnosis.Diagnosis.

Criteria for Diagnosis.Cardinal signs of leprosy 1. Definite loss of sensation in hypopigmented or erythematous lesion.2. Thickened peripheral nerve with loss of sensation & or weakness of muscles supplied.3. Presence of AFB in slit skin smear

Slit skin smearSlit skin smearIn smears M. leprae is quantified by the biopsy index (BI), a logarithmic scale as to the numbers of bacilli per oil immersion field (OIF) BI of 6 is 1000 or more bacilli/OIF

5 is 100-1000 bacilli/OIF

4 is 10-100 bacilli/OIF

3 is 1-10 bacilli/OIF

2 is 1 bacillus/1–10 OIF

1 is 1 bacillus/ 10-100OIF

0 is no bacillus/100 OIF

SSS only detect bacilli present at a concentration greater than 10 ‘4/ g tissue, and so cannot be used as a test of microbiological cure

Slit skin smearSlit skin smear

detected by modified Ziehl-Neelsen stain the bacilli a bright red color.

Lesions and cooler areas of the skin, such as the earlobes, elbows, and knees, and stained with acid-fast stains

An incision 5 mm long and 3 mm deep-blade is turned at right angles to cut

Fluid and pulp from the dermis.

Histopathology.Histopathology.

• Biopsies - confirmation of diagnosis & classification of leprosy.

• histologic features of disease correlate with the clinical pattern of disease.

Lepromin or Mitsuda test.Lepromin or Mitsuda test.

Lepromin, 0.1 mL, is injected intradermally.

reaction is read at -48 h (Fernandez reaction) - 3-4 weeks (Mitsuda reaction). Fernandez - delayed hypersensitivity to the soluble components of Lepromin.

Mitsuda reaction is a granulomatous response to particulate antigenic material

All TT and most BT( 85%) are positive (3 mm or more of induration at 21 days)

BB through LLp are negative (< 3 mm).

not useful in diagnosis, but can be of value in classification of patients.

DIFFERENTIIAL DIAG NOSIS.• consider leprosy as a cause of peripheral neuropathy.

Macular & Patch lesions Papular to Nodular lesions Birthmarks Cutaneous leishmaniasis Vitiligo PKDL

pityriasis alba lymphomas pityriasis versicolor Plaques and annular lesions Tinea corporis granuloma multiforme sarcoidosis cutaneous tuberculosis

TREATMENTTREATMENT

Main principles of treatment.

Stop the infection with chemotherapy.

Treat reactions and reduce the risk of nerve damage.

Treat the complications of nerve damage.

Rehabilitate the patient socially and psychologically.

PB – MDT regimen

Child <10yrs Rifampicin 300mg monthly Dapsone 25mg daily

10 – 14yrs Rifampicin 450mg monthly Dapsone 50mg daily

>15yrs Rifampicin 600mg monthly Dapsone 100mg daily

MB – MDT regimen

Child <10yrsRifampicin 300mg monthlyClofazimine 100mg monthlyClofazimine 50mg 2x/weekDapsone 25mg daily

MB – MDT regimen

10 – 14yrsRifampicin 450mg monthlyClofazimine 150mg monthlyClofazimine 50mg every other

dayDapsone 50mg daily

MB – MDT regimen

>15yrsRifampicin 600mg monthlyClofazimine 300mg monthlyClofazimine 50mg Dapsone 100mg daily

Reactional statesReactional states•Problems – related Leprosy

•Immunologicaly driven distinctive, tissue destructive ,inflammatory processes that appears suddenly in any form of leprosy

•Precipitating factor MDT Pregnancy Inter current infections Vaccination (BCG)

•Usually as complications during treatment but they may occur before treatment or after

•Reactional states Type-1 (Reversal ) Type-2 (ENL)

TYPE I REACTI0N TYPE I REACTI0N

• enhanced T cell-mediated immune response to M. leprae (Type4 DTH)•increased numbers of CD4+ and IL-2producing cells in granulomas, and local production of cytokines such as IFN-y &TNF-a.

•can occur spontaneously as presenting disease •Most common in the first year of treatment(peak time 1st 6 months of Rx) or well after treatment has stopped.

•Particularly common in BL patients, but seen in BB,or BT patient.

TYPE -1 REACTION TYPE -1 REACTION

Clinically - Existing skin lesions become erythematous or edematous and may desquamate.

-new lesions can appear

In severe cases, ulceration can occur

Often multiple

edema of face, hands or feet is the presenting symptom,

TYPE -1 REACTION TYPE -1 REACTION

Often associated with neuritis (severe).• Nerves often become tender with/out loss of sensory and motor fun

constitutional symptoms are unusual.

ERYTHEMA NODOSUM LEPROSUMERYTHEMA NODOSUM LEPROSUM( TYPE 2 REACTI0N( TYPE 2 REACTI0N))

•regarded as an immune complex disorder.•supported by the presence of immunoglobulin and complement in the lesions and circulating immune complexes.

•occurs most often in LL, in up to 75 percent of cases,but can occur in BL

•occur before, during, or after chemotherapy.

•median time of onset is 1 year after onset of treatment.

ERYTHEMA NODOSUM LEPROSUM (cont’d)ERYTHEMA NODOSUM LEPROSUM (cont’d)

•Clinically-crops of new painful and tender bright- pink,dermal and subcutaneous nodules arising in clinically normal skin

•Lesions- targetoid, vesicular, pustular, ulcerative,or necrotic.

•Involvement of both upper and lower extremities is the rule.

•favor the extensor arms and medial thighs, face

ERYTHEMA NODOSUM LEPROSUM ERYTHEMA NODOSUM LEPROSUM

systemic symptoms- fever , malaise, anorexia

Arthralgias and arthritis are more common in ENL than -- neuritis, adenitis,

orchitis/ epididymitis, uveitis & iritis.

In severely involved patients, episodes can be frequent to virtually unremitting. -Chronic ENL -.

MANAGEMENT OF REACTIONSMANAGEMENT OF REACTIONSAIM controlling acute inflammation. easing pain. reversing progressive nerve and eye damage reassuring the patient.

Multidrug therapy should be continued.

Type-1 (Reversal) Reaction

mild reactions –(oedema & erythma skin lesions only) without neurologic complications or severe systemic symptoms or findings.

Treatment may be supportive. Bed res t/ASA or NSAID Examined P 1 week- Sn of rxn –Rx should Continued for another week Mild rxn > 6 weeks –severe

Type 1 Reaction.(Rx)Type 1 Reaction.(Rx)Severe rxn starting at a dose of 40 to 60 mg/day(0.5-1 mg/kg)

duration are determined by the clinical course of the reaction.

Once reaction is controlled, the prednisone may need to be tapered slowly-over months

.

Type 1 Reaction Rx Type 1 Reaction Rx •Nerve abscesses - need to be surgically drained immediately

•response of neuritis is not prompt rest & splinting of affected extremities

•Clofazimine

•Cyclosporin -(5-10mg/kg) •MTX

TYPE 2 REACTION TYPE 2 REACTION •Thalidomide treatment of choice.•initial recommended dosage is up to 400 mg/day (>50 kg)•milder cases, treatment may be started (100 to 200 mg/day)

•Systemic corticosteroids are also effective•high-dose steroids (80-mg daily,tapered down rapidly)•ENL frequently recurs, steroid dependency can easily develop

TYPE 2 REACTION TYPE 2 REACTION •Clofazimine in higher doses (up to 300 mg/day) is effective in ENL, and may be used alone or to reduce corticosteroid or thalidomide doses.

•Combination pentoxifylline and clofazamine•Pentoxyfylline

•Acute irido cyclitis - 4-hourly instillation of 1% hydrocortisone eye drops and 1%

atropine drops twice daily.

Differentiation b/n Relapse & ReactionDifferentiation b/n Relapse & Reaction

Criteria Relapse Reaction

onset P Rx >2 years <2 years

Development slow sudden

Pain/Tenderness No frequent

General condition Not affected affected Ulceration Unusual Common BI Increase Vs previous lower Vs pre

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