1. SEMINAR Dr. AAKANKSHA GODIYAL

2. LEPROSY

3. Definition  A chronic granulomatous infection and its sequalae caused by Mycobacterium leprae affecting skin and nerves primarily  More than 800,000 new cases detected worldwise annually

4. History  Ancient disease  Writings from India describe similar illness as early as 6 th century BC  Imported to Europe by troops of Alexander.European epidemic peaked in 13 th century  French settlers took it to Canada and black slaves to America

5.  ARMAUER HANSEN of Norway attributed it to M.leprae in 1873  Effective chemotherapy began with sulfones in 1943  Rifampicin introduced in 1970  Grown in mouse footpad in 1961 & in nine banded armadillo in 1971  Sequence of genome published in 2001

6. EPIDEMIOLOGY  Endemic in all continents except Antarctica  2/3 rd of world’s leprosy burden in Indian subcontinent  Incidence:800,000 per year  Not always a tropical disease; was endemic in norway till 20 th century  IP=2 to 5 yr for tuberculoid & 8 to 12 yr for lepromatous cases

7.  Loss of 1 million disability adjusted life years  Majority of cases before 35 yr age with median age less for tuberculoid cases  Excess of male cases regularly found  Clustering of cases well recognised  HLA association

8.  HLA-DR2/DR3 occur at higher frequency in TT/BT patients  HLA-DQ1 increase susceptibility to BL/LL leprosy  In South India assoc. found between paucibacillary leprosy and 10p13 chromosome  Main source of infection- nasal discharge from untreated LL patients  Not excreted by skin

9. AETIOLOGY  Classified under order Actinomycetalis and family Mycobacteriacae  Straight/slightly curved rods with parallel sides and round ends  Gram +ve, acid fast. Characteristically acid fastness lost with pyridine extraction  Obligate intracellular parasite especially in macrophages  Noncultivable.. Grows at 30-33 degree centigrade  Doubling time= 12-13 days

10.  Genome of M.leprae(3.27 megabases) shorter than M.tuberculosis(4.41 megabases)  ULTRASTRUCTURE  Following components from inside out:  Cytoplasm  Trilaminar plasma membrane

11.  Cell wall is 20 nm thick & electron dense. Consists of peptidoglycan covalently attached to arabinogalactan polymer modified by branched chain mycolic acid. Lipoarabinomannan is another important component  Capsule is electron transparent due to copious amounts of lipid- phthiocerol dimycocerosate & phenolic glycolipid

12.  PGL-1 is species specific and immunogenic  Entry into nerves mediated by binding of PGL1 to laminin 2 in basal lamina of Schwann cells

15. PATHOLOGIC SPECTRUM OF LEPROSY  Lepra bacilli is non toxic. Clinicopathologic manifestations are result of immunopathology  RIDLEY JOPLING ciassification defines categories along a spectrum depending on clinical,histopathological, immunological indices:  TT,BT,BB,BL,LL  TT and polar LL patients are stable while others move in either direction according to host response & treatment

18. PATHOLOGY  TUBERCULOID LEPROSY:Tuberculoid granulomas found which tend to collect in foci around neurovascular elements.  Each focus cosists of epitheloid cells at centre with surrounding zone of lymphocytes. Langhans giant cells sometimes found  Some of the foci invade papillary zone and even erode basal layer

19.  Bacilli not seen  Dermal nerves are either completely destroyed or swollen by epithelioid cell granuloma. Occasionally there may be caseation within a nerve

22. BORDERLINE LEPROSY  BT:  Epithelioid cell granuloma more diffuse with a free but narrow papillary zone. Giant cells tend to be of foreign body type.  Dermal nerves are moderately swollen by cellular infiltration or schwann cell proliferation  Bacilli absent from dermis but likely to be found witin dermal nerves

23.  Granulomas follow neurovascular bundles, sweat glands or erector pili muscles

24. BB  Diffuse epithlioid cell granuloma with scanty lymphocytes and no giant cells  Papillary zone is clear and dermal nerves show slight swelling with cellular infiltrate  Bacilli present within dermal nerves & dermis in modest numbers

25. BL  There is macrophage granuloma in which some cells show slight foamy changes. Lymphocytes present in dense clumps or widely distributed in parts of granuloma. Occasionally epithelioid cells seen  Papillary zone is free  Bacilli are plentiful-singly or in clumps

26.  Dermal nerves contain some cellular infiltrate & perineurium may have laminated appearance(onion skin perineurium)

27. LEPROMATOUS LEPROSY  Extensive cellular infiltrate that is separated from flattened epidermis by Grenz zone of normal collagen  In early lesions macrophages have mixed population of solid and fragmented bacilli.Solid bacilli are packed like cigars. Bacilli may be seen in endothelial cells  No epithelioid cells. Lymphocytes not prominent. Plasma cells may be seen

29.  In time degenerated bacilli accumulate in macrophages so called virchow or lepra cells which have foamy cytoplasm. In chronic lesions bacilli are disposed in large basiophilic clumps called globi  Dermal nerves are well preserved & contain large no of bacilli. Slowly become fibrotic

31. LUCIO LEPROSY  Show similar histological features but with characteristic heavy bacillation of small blood vessels in skin causing obliterative angiitis and ischaemic epidermal necrosis

33. Histoid leprosy  Shows highest load of bacilli & majority are solid staining arranged in clumps like sheaves of wheat. Macrophages show storiform pattern similar to fibrohistiocytoma

35. Type 1 reaction  Edema within & around granuloma  In upgrading reaction granulomas become more epithelioid & langhans giant cells are larger. There may be erosion of granuloma into lower epidermis  Fibrinoid necrosis within granulomas or in dermal nerves

37.  Downgrading reaction: necrosis less common. Density of bacilli increases  Multibacillary patients who upgrade on therapy show old foamy macrophages mixed with new epithelioid cell granulomas

38. Type2 reaction(ENL)  Lesions are foci of acute inflammation on chronic multibacillary leprosy. Neutrophils may be scanty or abundant to form abscess. Foamy macrophages with fragmented bacilli abundant

40. Lucio reaction  Endothelial proliferation leading to luminal obliteration seen with thrombosis of medium sized vessels in dermis & subcutis  Dense aggregates of AFB in walls of normal appearing vessels & vessels with proliferative changes

41. Indeterminate leprosy  Mild lymphocyte & macrophage accumulation around neurovascular bundles, sweat glands & erector pili muscles. No epithelioid cell granulomas. Schwann cell hyperplasia may be seen  Diagnosis rests on finding 1/more AFB in sites of predilection- erector pili muscles, just beneath epidermis or around a vessel

43. CLINICAL FEATURES  Indeterminate Leprosy: Lesions found on face, extensor surface of limbs or buttocks.  Consist of one or more slightly hyperpigmented or erythematous machules with poorly defined margins.  Hair growth and nerve functions are normal.  Found usually in children whose immune status is yet to be determined. Smears are negative. Sometimes thickened nerve is palpable.

45. POLAR TUBERCULOID  Primary lesion is a plaque assuming an annular configuration. Both the borders are sharply marginated.  Lesion is indurated, elevated, scaly, dry, hairless and hypopigmented.  Nearby sensory nerve may or may not be enlarged but the lesion is anaesthetic & anhidrotic.  Usually solitary.

46.  Spontaneous cure is known.  Upper limit of 10 cm on lesion size.

49. BORDERLINE TUBERCULOID  Primary lesion are plaques and papules.  Annular configuration is common with both borders sharply defined but incomplete annular lesions may be seen. Satellite lesions present.  Little scaling, less erythema, less induration, size more than 10 cm.  Multiple asymmetric lesions are a rule.  Loss of sensation in skin lesion, nerve trunk enlargement and palsies seen.

50.  Nerve trunk involvement asymmetric and not more than 2.  Nerve abscesses are most often seen in males with BT disease.

55. MID BORDERLINE  Immunological midpoint  Characteristic lesions are annular with sharply marginated interior and exterior margins or large plaques with islands of normal skin within the plaque giving a Swiss cheese appearance or a classic dimorphic lesion.  Because of instability BB is shortlived and rarely seen.

57. BORDERLINE LEPROMATOUS  Highly variable in clinical expression  In 1/3 rd patients classic dimorphic lesion seen. Annular lesions with both borders sharply defined uncommon but when they occur lepromatous like papules & nodules seen.  Lesions may be hypoaesthetic/anaesthetic but not necessarily so.  Nerve trunk palsies have highest prevalence in BL.

58.  Untreated BL has a relentless progression. When disease is extensive acral distal symmetric anaesthesia may be present.  Course altered by reactional states.

62. LEPROMATOUS LEPROSY  Poorly defined skin coloured nodules are the most characteristic & symmetrically distributed.  Diffuse dermal infiltration is always present, manifested by widening of nasal root and fusiform swelling of fingers.  Skin over forehead thickened causing Leonine facies. Earlobes thickened.  Ciliary or superciliary madarosis +

63.  Macules are small, numerous, erythematous, vague and shiny with no loss of sensation or hair growth. Papules may also be present  Sometimes, all 3 lesions may be present  Chronic edema of leg is usual  Nerve trunk palsies less common than in BL. Acral distal symmetric(glove & stocking) anaesthesia seen

64.  Systemic associations  Nose may collapse with septal perforation, voice may become hoarse, upper incisor teeth may loosen and fall off  Shortening of fingers and toes due to repeated trauma  Anaesthetic skin liable to blister and ulceration  Eyes- superficial punctate keratitis, insidious iritis (beginning as iris pearls)

65.  Damage to cranial nerve V & VII- corneal insensitivity and lag ophthalmos predispose cornea to injuries  Bone changes occur late- periostitis of bones of leg and forearms, atrophy of distal phalanges of hands & atrophy of phalanges, metatarsal & tarsal bones of feet  In skull atrophy of anterior nasal spine and of maxillary alveolar process lead to facies leprosa

66.  Kidney- renal damage important cause of morbidity & mortality (renal amyloidosis, glomerulonephritis, etc)

72. PREGNANCY & LEPROSY  1. Worsening of leprosy status (third trimester of pregnancy)  2. Type I reaction (during first six months of lactation)  3. Type II reaction (in third trimester & first six months of lactation)  50 % suffer deterioration of nerve function

73. LUCIO LEPROSY  Diffuse non nodular type. Described by Lucio and Alvarado in Mexico.  hands, wide spread sensory loss. Shiny thickened skin, body hair loss, puffy  Eyes- shiny appearence  Anaemia, edema, ulceration of both legs  Nasal symptoms present  No motor palsies and eyes not damaged.

75. HISTOID HANSENS  Term introduced by Wade  Applied to firm erythematous round shiny glistering nodules which appear on skin of patients whose disease is relapsing either because they have stopped treatment or because M. leprae has become drug resistant  Histoid nodules contain elongated spindle shaped histiocytes with bacilli within them

76. TYPE I LEPRA REACTION  Delayed (type IV) hypersensitivity reaction  Antigens from breaking down of lepra bacilli react with T-lymphocytes  Seen in borderline patients  Increase in CMI associated with treatment known as reversal reaction whereas reduction in immunity called downgrading reaction

77.  Upgrading most common during first six months of treatment  LLs->BL->BB->BT->TTs  Rapidly developing change in some/all skin lesions- become erythematous, shiny, warm and tender. Sometimes necrosis occurs leading to ulceration. Lesions desquamate as the subside

78.  Systemic features less common  Nerve involvement- swelling of one or more nerves with pain and tenderness  Most serious complication is motor disturbance and nerves at risk are ulnar, lateral popliteal and facial  Paralysis can recover with prompt treatment

79.  Edema of hands, feet or face  Tenderness of palms and soles

82. TYPE II LEPRA REACTION  Is an immune complex syndrome (type III) hypersensitivity reaction  Occurs almost always LLp/LLs and occasionally in BL  No change of leprosy lesions but crops of brightly red nodules seen which come and go  Systemic disturbance usual  Unusual for it to occur during first six months of treatment

83.  ENL lesions tend to be bilaterally symmetrical. Often tender and blanch with light pressure. Evanescent lasting two- three days  Commonly on face, arms and thighs. Leave bluish stain as they fade  In severe reactions lesions may become vesicular and break down (erythema necroticans)  Other features- neuritis, myositis, arthritis, rhinitis, acute iritis, dactylitis, epididymoorchitis and proteinuria

84.  Factors precipitating ENL  Physical/ mental stress  Immunization  Intercurrent infection/injury/surgery  Pregnancy/parturition  Ingestion of KI besides anti-leprosy drugs

87. LUCIO PHENOMENON  Confined to diffuse non-nodular LL leprosy chiefly encountered in Mexicans  Unique feature- seen only in untreated patients  Painful red patches appear on the skin especially extremities, become purpuric, ulcerate and finally develop an eschar which falls off to leave a superficial atrophic scar  Face and trunk are spared. Patients afebrile

88.  Steroids- show good effect  Thalidomide of no value  Good results with Dapsone  Excellent results with Rifampicin

90. DIFFERENTIAL DIAGNOSIS  I. Neurological conditions PALPABLE N. THICKENING WITHOUT ANAESTHESIA/SIGNS OF N. DAMAGE PALPABLE N. THICKENING WITHOUT ANAESTHESIA/SIGNS OF N. DAMAGE 1. Excessive muscular development 1. Excessive muscular development 2. Pachydermoperiostitis 2. Pachydermoperiostitis

91. PALPABLE N. THICKENING WITH REGIONAL ANAESTHESIA WITH/WITHOUT MUSCLE WASTING PALPABLE N. THICKENING WITH REGIONAL ANAESTHESIA WITH/WITHOUT MUSCLE WASTING 1. Primary amyloidosis of peripheral nerves 2. Familial hypertrophic interstitial neuritis

92. REGIONAL ANAESTHESIA WITH/WITHOUT MUSCLE WASTING BUT WITH NERVE THICKENING REGIONAL ANAESTHESIA WITH/WITHOUT MUSCLE WASTING BUT WITH NERVE THICKENING 1. Recurrent/chronic progressive polyneuritis 2. Peroneal muscular atrophy (charcot-marie-tooth syndrome)

93. REGIONAL ANAESTHESIA WITH/WITHOUT MUSCLE WASTING BUT WITHOUT NERVE THICKENING REGIONAL ANAESTHESIA WITH/WITHOUT MUSCLE WASTING BUT WITHOUT NERVE THICKENING 1. Syringomyelia 2. Tabes dorsalis 3. Peripheral neuropathies 4. Hereditary sensory radicular neuropathy 5. Congenital indifference to pain

94.  II. DERMATOLOGICAL CONDITIONS None of the conditions listed below have all the three features of sensory loss, nerve thickening and +ve skin smear for AFB None of the conditions listed below have all the three features of sensory loss, nerve thickening and +ve skin smear for AFB A. Flat and hypopigmented lesions 1. Morphoea 2. Onchocerciasis 3. Pityriasis alba 4. Tenia versicolor

95. 5. Post kala azar dermal leishmaniasis 6. Yaws 7. Vitiligo B. Raised and pigmented lesions 1. Follicular mucinosis (alopecia mucinosa) 2. Granuloma annulare 3. Granuloma multiforme 4. Gyrate erythemas 5. Kaposi’s sarcoma 6. Cutaneous leishmaniasis 7. Lupus erythematosus

96. 8. Lupus vulgaris 9. Mycobacterium marinum infection 10. Mycosis fungoides 11. Neurofibromatosis 12. P.rosea 13. Tinea corporis c. Generalized thickening of skin 1. Systemic sclerosis 2. Myxoedema 3. Pachydermoperiostosis

97. CONCLUSION