Leprosy

undergraduate class

1. Leprosy (Hansen's Disease)

2. Discovered by Gerhard Armauer Hansen in 1873 Global Project on the History of Leprosy http://www.leprosyhistory.org/graphics/gallery/hansen.jpg

3. Introduction Leprosy, first described in ancient Indian texts from the sixth century B.C., is a nonfatal, chronic infectious disease caused by Mycobacterium leprae , whose clinical manifestations are largely confined to the skin, peripheral nervous system, upper respiratory tract, eyes, and testes. The unique tropism of M. leprae for peripheral nerves (from large nerve trunks to microscopic dermal nerves) and certain immunologically mediated reactional states are the major causes of morbidity in leprosy.

4. Bacteria Resides in Cooler Parts of the Body http://www.nlm.nih.gov Skin Peripheral Nerves

5. Etiology M. leprae is an obligate intracellular bacillus (0.3–1 m wide and 1–8 m long) that is confined to humans, armadillos in certain locales The organism is acid-fast, indistinguishable microscopically from other mycobacteria , and ideally detected in tissue sections by a modified Fite stain. The morphologic index (MI), a measure of the number of acid-fast bacilli (AFB) in skin scrapings that stain uniformly bright, correlates with viability.

6. Leprosy is caused by Mycobacterium leprae Scollard, DM et al. 2006. “The continuing challenges of leprosy.” Clinical microbiology reviews 19, no. 2: 338-81.

7. The bacteriologic index (BI), a logarithmic-scaled measure of the density of M. leprae in the dermis, may be as high as 4–6+ in untreated patients A rising MI or BI suggests relapse and perhaps—if the patient is being treated—drug resistance.

8. The unique trisaccharide of M. leprae binds to the basal lamina of Schwann cells; this interaction is probably relevant to the fact that M. leprae is the only bacterium to invade peripheral nerves

9. Transmission Nasal/oral Droplets Dermal Inoculations Materno -fetal milk

10. Classification Lepromatous (low resistance) Tuberculoid ( high resistance) Polar forms: opposite poles

11. The incubation period prior to manifestation of clinical disease can vary between 2 and 40 years, although it is generally 5–7 years in duration. Ridley and jopling s classification : polar tuberculoid (TT) borderline tuberculoid (BT) mid-borderline (BB, which is rarely encountered) Lepromatous indefinite (LI) borderline lepromatous (BL) polar lepromatous (LL)

12. Tuberculoid Leprosy these forms of leprosy result in symptoms confined to the skin and peripheral nerves. The skin lesions of tuberculoid leprosy consist of one or a few hypopigmented macules or plaques that are sharply demarcated and hypesthetic , often have erythematous or raised borders, and are devoid of the normal skin organs (sweat glands and hair follicles) and thus are dry, scaly, and anhidrotic . AFB are generally absent or few in number.

13. Tuberculoid leprosy patients may have asymmetric enlargement of one or a few peripheral nerves. those most commonly affected are the ulnar , posterior auricular, peroneal , and posterior tibial nerves, with associated hypesthesia and myopathy .

14. In tuberculoid leprosy, T cells breach the perineurium , and destruction of Schwann cells and axons may be evident, resulting in fibrosis of the epineurium , replacement of the endoneurium with epithelial granulomas , and occasionally caseous necrosis. Such invasion and destruction of nerves in the dermis by T cells are pathognomonic for leprosy.

15. Lepromatous Leprosy present with symmetrically distributed skin nodules raised plaques, or diffuse dermal infiltration, which, when on the face, results in leonine facies . Late manifestations include loss of eyebrows (initially the lateral margins only) and eyelashes, pendulous earlobes, and dry scaling skin, particularly on the feet. In LL leprosy, bacilli are numerous in the skin (as many as 10 9 /g), where they are often found in large clumps ( globi ), and in peripheral nerves, where they initially invade Schwann cells, resulting in foamy degenerative myelination and axonal degeneration and later in Wallerian degeneration.

16. Reactional States Lepra reactions comprise several common immunologically mediated inflammatory states that cause considerable morbidity.

17. Type 1 Lepra Reactions (Downgrading and Reversal Reactions) Type 1 lepra reactions occur in almost half of patients with borderline forms of leprosy but not in patients with pure lepromatous disease. Manifestations include classic signs of inflammation within previously involved macules , papules, and plaques and, on occasion, the appearance of new skin lesions, neuritis, and (less commonly) fever—generally low-grade. The nerve trunk most commonly involved in this process is the ulnar nerve at the elbow, which may be painful and exquisitely tender. If patients with affected nerves are not treated promptly with glucocorticoids irreversible nerve damage may result in as little as 24 h. The most dramatic manifestation is footdrop , which occurs when the peroneal nerve is involved

18. When type 1 lepra reactions precede the initiation of appropriate antimicrobial therapy, they are termed downgrading reactions , and the case becomes histologically more lepromatous ; when they occur after the initiation of therapy, they are termed reversal reactions , and the case becomes more tuberculoid .

19. Type 2 Lepra Reactions: Erythema Nodosum Leprosum occurs exclusively in patients near the lepromatous end of the leprosy spectrum (BL-LL), affecting nearly 50% of this group. Although ENL may precede leprosy diagnosis and initiation of therapy (sometimes, in fact, prompting the diagnosis), in 90% of cases it follows the institution of chemotherapy, generally within 2 years. The most common features of ENL are crops of painful erythematous papules that resolve spontaneously in a few days to a week but may recur; malaise; and fever that can be profound.

20. ENL

21. Lucio's Phenomenon Patients with this reaction develop recurrent crops of large, sharply marginated , ulcerative lesions—particularly on the lower extremities—that may be generalized and, when so, are frequently fatal as a result of secondary infection and consequent septic bacteremia . Histologically , the lesions are characterized by ischemic necrosis of the epidermis and superficial dermis, heavy parasitism of endothelial cells with AFB, and endothelial proliferation and thrombus formation in the larger vessels of the deeper dermis. Like ENL, the Lucio phenomenon is probably mediated by immune complexes

22. Complications The Extremities consequence of neuropathy leading to insensitivity and myopathy Plantar ulceration Foot drop The loss of distal digits

23. The Nose In lepromatous leprosy, bacillary invasion of the nasal mucosa can result in chronic nasal congestion and epistaxis . Saline nose drops may relieve these symptoms. Long-untreated LL leprosy may further result in destruction of the nasal cartilage, with consequent saddle-nose deformity or anosmia (more common in the preantibiotic era than at present).

24. The Eye Owing to cranial nerve palsies, lagophthalmos and corneal insensitivity may complicate leprosy, resulting in trauma, secondary infection, and (without treatment) corneal ulcerations and opacities. in LL leprosy, the anterior chamber of the eye is invaded by bacilli, and ENL may result in uveitis , with consequent cataracts and glaucoma. Thus leprosy is a major cause of blindness in the developing world. Slit-lamp evaluation of LL patients often reveals "corneal beading," representing globi of M. leprae

25. The Testes M. leprae invades the testes, while ENL may cause orchitis . Thus males with lepromatous leprosy often manifest mild to severe testicular dysfunction, with an elevation of luteinizing and follicle-stimulating hormones, decreased testosterone, and aspermia or hypospermia in 85% of LL patients but in only 25% of BL patients. LL patients may become impotent and infertile. Impotence is sometimes responsive to testosterone replacement.

26. Amyloidosis Secondary amyloidosis is a complication of LL leprosy and ENL that is encountered infrequently in the antibiotic era. This complication may result in abnormalities of hepatic and particularly renal function. Nerve Abscesses Patients with various forms of leprosy, but particularly those with the BT form, may develop abscesses of nerves (most commonly the ulnar ) with an adjacent cellulitic appearance of the skin. In such conditions, the affected nerve is swollen and exquisitely tender. Although glucocorticoids may reduce signs of inflammation, rapid surgical decompression is necessary to prevent irreversible sequelae

27. Symptoms & Diagnosis: (1) Skin Lesions Worobec, Sophie M. 2009. “Treatment of leprosy/Hansen's disease in the early 21st century.” Dermatologic therapy 22, no. 6: 518-37.

28. Global Project on the History of Leprosy http://www.leprosyhistory.org/graphics/gallery/mleprae.jpg Symptoms & Diagnosis: (2) Skin Smear Tests Ziehl Neelsen Carbol Fuchsin Stain (ZNCF)

29. Immunocompromised individuals are more susceptible to disease

30. Mechanism of Nerve Damage Scollard, DM et al. 2006. “The continuing challenges of leprosy.” Clinical microbiology reviews 19, no. 2: 338-81. Entry Through Blood Vessels 2. Inflammatory Response 3. Demyelination

31. Sensory Loss Paralysis Deformities Outcomes of Nerve Damage Leprosy: eMedicine Infectious Diseases http://emedicine.medscape.com/article/220455-overview

32. Sensory Loss Can Lead to Secondary Infections and Severe Deformities International Federation of Anti-Leprosy Associations (ILEP) http://www.ilep.org.uk/en/

33. Tuberculoid leprosy

34. Lepromatous leprosy

35. Lepromin test Delayed hypersensitivity reaction An early positive reaction appearing as an indurated area in 24 hrs – fernandez reaction A delayed granulomatous lesion appearing after 3 weeks – mitsuda reaction