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Quick Reference - High-Yield Exam Points

• Type 1 = DTH (Type IV), borderline types, existing lesions inflame, neuritis is the emergency → Prednisolone
• Type 2 = Immune complex (Type III), BL/LL only, new evanescent nodules, systemic → Thalidomide + Prednisolone
• Lucio = Type 3, only in DLL/M. lepromatosis/Mexico, angular purpuric ulcers ascending, endothelial cell injury, doesn't respond to steroids or thalidomide - MDT only

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Q6. Classify Lepra Reaction. Describe Lucio Phenomenon. [10 marks]

CLASSIFICATION OF LEPRA REACTIONS

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TYPE 1 REACTION (Reversal Reaction)

• Existing skin lesions suddenly become erythematous, edematous, warm, and tender ("hot lesions")
• New erythematous plaques may erupt
• Acute neuritis is the hallmark - peripheral nerve trunks become enlarged, exquisitely tender, and painful
• Sudden loss of nerve function: sensory (anesthesia), motor (paralysis), or autonomic (anhidrosis)
• Silent neuritis (quiet nerve paralysis): nerve damage without pain/swelling - particularly dangerous as patient has no warning
• No systemic symptoms (no fever, no visceral involvement)

• Loss of sensation or muscle weakness in nerve distribution
• Pain or tenderness in a nerve trunk
• Silent neuritis
• Red, swollen patch on face or overlying a major nerve trunk
• Ulceration of a skin lesion
• Marked edema of hands, feet, or face

• Drug of choice: Prednisolone 40-60 mg/day (1-2 mg/kg/day) with gradual taper over 12 weeks
• Mild reactions: NSAIDs only
• MDT must be continued throughout (never stop)
• Physiotherapy, nerve decompression surgery for non-responders

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TYPE 2 REACTION (Erythema Nodosum Leprosum - ENL)

• Crops of evanescent, erythematous, tender subcutaneous nodules (1-2 cm), especially on face, arms, and legs - bilaterally symmetrical
• Nodules are "better felt than seen," resolve in a few days even untreated, but recur episodically
• Prominent systemic features: high fever, malaise, myalgia, joint pains
• Neuritis: present but less acute/severe than Type 1
• Multi-organ involvement: iritis/iridocyclitis, orchitis/epididymitis, glomerulonephritis, lymphadenopathy, hepatosplenomegaly, osteitis

• Mild ENL: NSAIDs (aspirin), analgesics
• Severe/recurrent ENL: Thalidomide 100-400 mg/day (drug of choice; absolutely contraindicated in pregnancy) AND/OR prednisolone 1-2 mg/kg/day
• Clofazimine 300 mg/day for chronic recurrent ENL (takes 4-6 weeks for full effect; never use as sole agent in severe acute ENL)
• MDT continues throughout

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Comparison Table: Type 1 vs Type 2

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LUCIO PHENOMENON [4 marks]

Definition

Epidemiology

• Almost exclusively reported from Mexico and Costa Rica; rare elsewhere
• Associated with Mycobacterium lepromatosis (a second mycobacterium distinct from M. leprae) which specifically infects endothelial cells in DLL patients

Background: Lucio (Diffuse) Leprosy

• Diffuse, non-nodular infiltration of skin giving a waxy, shiny appearance ("lepra bonita" - beautiful leprosy)
• Loss of all body hair (eyebrows, eyelashes, body hair - total madarosis)
• Diffuse infiltration of ear lobes and forehead
• Hoarse voice (laryngeal infiltration)
• Numbness and edema of hands and feet resembling myxedema
• No discrete nodules - this distinguishes it from classic LL

Pathogenesis

• Endothelial cell injury is the central pathogenetic event
• M. lepromatosis directly invades and multiplies within endothelial cells of dermal blood vessels
• This causes thrombosis, ischemia, and infarction of the dermis
• Results in necrotizing, ulcerating skin lesions

Clinical Features of the Phenomenon

• Multiple, well-defined, angular/jagged (not rounded) purpuric lesions
• Evolve into massive, necrotizing ulcerations
• Spread in a characteristic ascending pattern up the extremities
• Heal with atrophic (cigarette-paper) scarring
• Unlike ENL: no nodules, no lymphadenopathy, no arthritis
• Unlike Type 1 RR: no pre-existing discrete skin lesions

Histopathology

• Epidermal necrosis and dermal ischemic infarction
• Fibrin thrombi occluding superficial dermal vessels
• Massive bacillary load within endothelial cells (not just macrophages)
• True vasculopathy rather than panniculitis (which is seen in ENL)

Treatment

• Lucio phenomenon is poorly responsive to corticosteroids and does not respond to thalidomide
• The only effective treatment is MDT (rifampicin-based anti-leprosy chemotherapy)
• Combined with wound management for leg ulcers (debridement, dressings)
• High mortality in severe cases due to sepsis and extensive skin loss

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Q7. Describe Atypical Presentations of Lepromatous Leprosy [10 marks]

INTRODUCTION

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1. HISTOID LEPROSY (Wade's Histoid Leprosy)

• Have relapsed after dapsone monotherapy (classical context - dapsone resistance)
• Have received inadequate treatment
• Occasionally arise de novo in untreated patients

• Smooth, shiny, hemispherical dome-shaped nodules (soft to firm)
• May be superficial, subcutaneous, or deeply fixed
• Located on face, back, buttocks, extremities, and over bony prominences (especially elbows and knees)
• Lesions appear on otherwise normal-looking skin (not on background of diffuse infiltration) - key distinguishing feature
• Number varies from a few to hundreds

• Predominance of spindle-shaped (fusiform) histiocytic cells arranged in storiform/whorled pattern
• Unusually large numbers of solid acid-fast bacilli packed in globi
• Mimics many conditions: dermatofibroma, neurofibroma, xanthoma, smooth muscle tumor

• Very high bacillary load = active reservoir of transmission
• Requires high index of suspicion for diagnosis
• Must be treated with MDT with rifampicin as backbone

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2. DIFFUSE LEPROMATOUS LEPROSY (Lucio Leprosy / DLL)

• Waxy, shiny, smooth skin without discrete nodules - "lepra bonita" (beautiful leprosy)
• Diffuse infiltration of face (forehead, ear lobes), trunk, extremities
• Loss of all body hair (complete madarosis - eyebrows, eyelashes, axillary, pubic hair)
• Hoarse voice (laryngeal infiltration)
• Numbness and edema of hands and feet mimicking myxedema
• Subcutaneous nodules may mimic lipomas (major diagnostic pitfall)
• Prone to developing Lucio phenomenon (purpuric ulcers)

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3. PURE NEURITIC LEPROSY (Primary Neuritic Leprosy)

• Asymmetric peripheral nerve thickening (palpable thickened nerve)
• Sensory loss in nerve distribution without any visible skin lesion
• Up to one-third of patients later develop skin lesions (neuritic phase precedes cutaneous phase)
• Diagnosis requires nerve biopsy for confirmation

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4. LEPROSY PRESENTING AS SLE-LIKE SYNDROME

• Fusiform (spindle-shaped) fingers
• Swan neck deformity
• False-positive VDRL/RPR (biologic false positive - antibodies to M. leprae lipid antigens cross-react with cardiolipin)
• Antiphospholipid antibodies and lupus anticoagulant positivity
• Hypergammaglobulinemia
• Anemia of chronic disease

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5. LEPROMATOUS LEPROSY WITH FIRST PRESENTATION AS ENL

• In some patients, Type 2 reaction (ENL) is the presenting manifestation of leprosy - before the chronic skin patches are recognized
• Patient presents with fever, tender subcutaneous nodules, and systemic illness
• Can be mistaken for panniculitis, vasculitis, lymphoma, or sepsis
• Slit-skin smear and biopsy establish diagnosis

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6. EARLY MACULAR LL (Infiltrated Macular Variant)

• Very early LL lesions are faint, widely scattered, very poorly defined hypopigmented or slightly erythematous macules
• Lesions are so numerous and subtle that they may be dismissed as normal skin variation or post-inflammatory hypopigmentation
• Sensation is preserved (making clinical diagnosis difficult since the examiner expects anesthesia)
• SSS and biopsy essential

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7. LEPROSY-IRIS (Immune Reconstitution Inflammatory Syndrome)

• Seen in leprosy-HIV co-infected patients following initiation of HAART
• Restoration of immunity provokes a sudden Type 1 reaction
• Erythematous, edematous, ulcerating lesions and acute neuritis
• Unlike HIV-related opportunistic infections, leprosy course is not significantly altered by HIV itself - IRIS is the major complication

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8. LEPROMATOUS LEPROSY IN PREGNANCY

• Pregnancy causes suppression of CMI - leprosy becomes more active
• Can present as relapse or reactivation of previously treated/quiescent disease
• Transient exacerbation of neuropathy and reversal reactions can occur despite ongoing MDT
• Thalidomide absolutely contraindicated; clofazimine used cautiously (skin pigmentation of infant)

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Q8. Discuss Pathogenesis of Trophic Ulcer and Its Management [10 marks]

DEFINITION

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PATHOGENESIS [5 marks]

Step 1: Neural Invasion by M. leprae

• M. leprae has a unique predilection for Schwann cells of cool, superficial peripheral nerve trunks
• Enters Schwann cells via the PGL-1 - laminin-2 - alpha-dystroglycan receptor axis
• Granulomatous inflammation, demyelination, and axonal destruction follow
• The posterior tibial and common peroneal nerves of the lower limb are most vulnerable

Step 2: Loss of Protective Pain Sensation (Anesthesia)

• Destruction of small-diameter sensory fibers (C-fibers and A-delta) abolishes pain and temperature sensation
• This is the critical step: without pain, the foot's protective reflex is lost
• The patient continues walking on an injured foot because there is no pain signal

Step 3: Anhidrosis (Autonomic Failure)

• Loss of autonomic nerve fibers causes failure of sweat glands
• Skin becomes dry, anhidrotic, hyperkeratotic, and fissured
• Fissures act as entry points for bacteria and starting points for ulcers

Step 4: Biomechanical Stress and Abnormal Loading

• Motor nerve damage (peroneal nerve) causes muscle imbalance:
  • Foot drop, claw toes, collapse of plantar arch
  • Concentration of body weight on abnormal bony pressure points (metatarsal heads, heel)
• Sensory loss removes proprioception, further worsening gait mechanics

Step 5: Repetitive Microtrauma and Blister Formation

• With each step, concentrated pressure causes subepidermal hemorrhage and blistering at pressure points
• Blisters rupture → shallow erosions

Step 6: Secondary Bacterial Infection

• Skin barrier disruption + warm, moist environment + colonizing bacteria (Staphylococcus aureus, Streptococcus, Gram-negatives, anaerobes)
• Infection tracks downward: skin → subcutaneous tissue → fascia → periosteum → bone

Step 7: Deep Ulceration and Osteomyelitis

• Untreated infection → osteomyelitis with bone destruction, periosteal reaction, and sequestrum formation
• Bone resorption leads to shortening and destruction of digits
• Chronic granulation tissue forms; healing is prevented by continued pressure

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CLINICAL FEATURES

• Site: Plantar surface over metatarsal heads (1st and 5th most common), heel, tips of claw toes
• Appearance: Thick hyperkeratotic callus rim surrounding a central, punched-out, deep ulcer
• Painless - hallmark feature (patient often unaware of the ulcer)
• May probe to bone in advanced cases
• Surrounding skin: anhidrotic, hyperkeratotic, fissured
• X-ray findings: periosteal reaction, osteolysis, sequestrum in osteomyelitis

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MANAGEMENT [5 marks]

A. Conservative (Non-Surgical) Management

• Complete bed rest until healing
• Total Contact Cast (TCC): Gold standard - custom-molded plaster cast that distributes weight evenly across the entire plantar surface
• Crutches, wheelchair for mobilization
• Patient education: every step taken on an active ulcer delays healing

• Daily soaking in clean water + mild soap (softens and removes callus and debris)
• Surgical debridement of callus rim and necrotic tissue (under aseptic conditions, scalpel)
• Antiseptic dressings: povidone-iodine, silver sulfadiazine
• Topical insulin dressings have shown evidence of accelerating wound healing
• Moist wound dressings (hydrogel, hydrocolloid) for clean granulating wounds

• For infected ulcers: systemic antibiotics guided by culture/sensitivity
• Empiric therapy: amoxicillin-clavulanate or ciprofloxacin for mild-moderate infection
• IV antibiotics (4-6 weeks) for osteomyelitis

• Continue or initiate MDT to halt further nerve damage
• Treat any concurrent lepra reaction with prednisolone

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B. Preventive (Long-Term Rehabilitation)

• Microcellular rubber (MCR) footwear - redistributes plantar pressure
• Rocker-bottom sole for foot drop
• Sandals with toe spacers for claw toes
• Footwear must be used for life

• Inspect feet daily (mirror for plantar surface)
• Never walk barefoot
• Moisturize skin daily (coconut oil, petroleum jelly) to prevent fissures
• Regular callus trimming at clinic

• Joint mobilization exercises to prevent contractures
• Muscle-strengthening exercises for residual motor function
• Gait retraining

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C. Surgical Management

• Debridement + split-thickness skin grafting for large, clean granulating wounds
• Sequestrectomy for chronic osteomyelitis
• Tendon transfer for foot drop (tibialis posterior transfer)
• Ray amputation for irreversible single-digit destruction
• Syme's amputation for severe, uncontrolled osteomyelitis
• Plantar fasciotomy for plantar contractures

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Q9. Describe Systemic Involvement of Lepromatous Leprosy (LL) [10 marks]

INTRODUCTION

1. Hematogenous bacillary dissemination - M. leprae spreads via blood to multiple cool organs
2. Granulomatous infiltration by foamy (lepra) macrophages in organ parenchyma
3. Type 2 reaction (ENL) - immune complex vasculitis causing acute multi-organ inflammation
4. Secondary AA amyloidosis - from sustained acute-phase response in chronic recurrent ENL

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ORGAN-BY-ORGAN INVOLVEMENT

1. UPPER RESPIRATORY TRACT AND LARYNX (Most Common)

• Nasal mucosa: earliest site of involvement; congestion, epistaxis, mucosal ulceration, nasal crusting
• Destruction of nasal septal cartilage (not bone initially) → saddle nose deformity (pathognomonic of LL)
• Loss of anterior nasal spine
• Laryngeal infiltration: hoarseness, leprous laryngitis; stridor in severe involvement; risk of upper airway obstruction
• Pharyngeal and palatal infiltration with thickened plaques

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2. EYES (10-50% of Patients; Major Cause of Blindness)

• Corneal nerve thickening - beaded nerves visible on slit-lamp (pathognomonic)
• Superficial punctate keratitis; interstitial keratitis
• Corneal hypoesthesia → exposure keratitis → corneal ulceration → blindness

• Iris pearls (miliary lepromas) - small white nodules on the pupillary margin of the iris - pathognomonic of LL
• Acute iritis/iridocyclitis during ENL reactions
• Posterior synechiae, secondary glaucoma, complicated cataract

• Lagophthalmos (inability to close eyelids fully) - due to facial (zygomatic branch) nerve palsy - most common cause of blindness in leprosy
• Madarosis (loss of eyebrows and eyelashes) - characteristic of LL
• Ectropion, entropion, trichiasis

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3. TESTES AND MALE REPRODUCTIVE SYSTEM

• M. leprae colonizes testes preferentially due to their lower temperature (ideal for bacillary growth)
• Bilateral leprous orchitis and epididymo-orchitis: painless, progressive
• Testicular fibrosis and atrophy
• Destruction of Leydig cells → reduced testosterone → hypergonadotrophic hypogonadism (raised FSH, raised LH, low testosterone)
• Clinical consequences: gynecomastia, impotence, infertility, small firm testes
• Note: Female reproductive organs are NOT significantly involved in leprosy (unlike males)

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4. KIDNEYS

• AA amyloidosis: most serious renal complication; sustained elevation of serum amyloid A protein from recurrent ENL drives amyloid deposition in glomeruli
• Clinical: proteinuria, nephrotic syndrome, progressive renal failure
• Glomerulonephritis during acute ENL: immune-complex deposition in glomerular basement membrane
• Interstitial nephritis from direct granulomatous infiltration
• Chronic renal failure is a leading cause of death in long-standing LL

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5. BONES AND JOINTS

• Phalangeal osteolysis: concentric bone absorption of phalanges of hands and feet → "pencil-and-cup" deformity, progressive shortening of digits
• This is distinct from trophic ulcer-related osteomyelitis (different mechanism)
• ENL arthritis: symmetrical, non-destructive polyarthritis during reactions (immune-complex mediated)
• Charcot's joint (neuropathic arthropathy): loss of proprioception causes joint destruction
• Periostitis of tibia and fibula during ENL
• Collapse of nasal bones (saddle nose)
• Resorption of anterior nasal spine and maxillary alveolar process (loss of upper teeth)

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6. LIVER AND SPLEEN

• Hepatomegaly and splenomegaly during ENL reactions
• Leprous hepatitis: granulomatous infiltration of liver; mild transaminase elevation; rarely clinically significant
• Diffuse infiltration of spleen by foamy macrophages; lepromas
• In advanced amyloidosis: hepatic and splenic amyloid deposition

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7. LYMPH NODES

• Generalized lymphadenopathy (especially inguinal and axillary)
• Leprous lymphadenitis: foamy macrophages packed with bacilli in lymph node sinuses
• Lymph node biopsy useful for diagnosis when skin smear is unavailable or negative

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8. PERIPHERAL NERVES

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9. CONSTITUTIONAL AND LABORATORY FEATURES

• Fever, malaise, weight loss (during ENL episodes)
• Anemia of chronic disease
• Hypergammaglobulinemia (polyclonal)
• False-positive VDRL (biologic false positive: anti-M. leprae antibodies cross-react with cardiolipin)
• Antiphospholipid antibodies and lupus anticoagulant positivity
• These serological abnormalities can mimic SLE (lepra-SLE syndrome)

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Q10. Short Notes [5 marks each]

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(a) MORPHOLOGICAL INDEX (MI) [5 marks]

Definition

Distinction from Bacterial Index (BI)

Criteria for a "Solid" (Viable) Bacillus

1. Uniformly stained from end to end (no unstained gaps)
2. Parallel sides (straight or gently curved)
3. Rounded ends
4. Length is at least twice the breadth (rod-shaped, not coccoid)

Normal Values and Reference Points

• Untreated multibacillary leprosy: MI = 1-5% (may reach 40% in highly active cases)
• After initiating effective MDT: MI = 0% within 3-4 weeks (due to rapid bactericidal action of rifampicin)
• BI may take 3-5 years to reach 0 after MDT
• MI = 0% → no viable bacilli → patient is no longer infectious

Clinical Utility

Procedure

• Slit-skin smear from ear lobule, forehead, and active lesions
• Stained by Ziehl-Neelsen (ZN) or Fite-Faraco method
• Count minimum 200 bacilli under oil immersion
• Record percentage that are morphologically solid

Limitations

• Requires experienced, trained microscopist
• Significant inter-observer variability
• Not routinely used in WHO field programs (BI remains the standard field tool)
• Being replaced in research settings by viability PCR

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(b) LEPROMIN TEST (Mitsuda Test) [5 marks]

Definition

Lepromin Preparation

• Standard (Dharmendra) lepromin: Chloroform-ether extracted, purified bacillary fraction
• Mitsuda lepromin (integral lepromin): Autoclaved suspension of M. leprae (1.6 × 10⁸ organisms/mL) from human leprous nodules or armadillo-derived tissue

Procedure

• Inject 0.1 mL of lepromin intradermally into the volar surface of the forearm
• Read at two time points:

Grading of Mitsuda Reaction

Correlation with Leprosy Spectrum

Critical Properties - What the Lepromin Test IS and IS NOT

1. A diagnostic test for leprosy (positive reactions occur in BCG-vaccinated individuals and in non-leprosy persons in endemic areas with subclinical exposure)
2. A test for recent exposure or active infection

1. A prognostic test - reflects the host's CMI status
2. An epidemiological tool - surveys population immunity
3. A research tool - classifies patients on the immunological spectrum

Prognostic Significance

• Mitsuda (+++) = intact CMI = resistant host = tendency toward tuberculoid (paucibacillary, self-healing) disease = good prognosis
• Mitsuda (-) = anergy = susceptible host = tendency toward lepromatous (multibacillary) disease = poor prognosis
• Fernandez reaction reflects pre-existing sensitization to mycobacterial antigens (less specific, also positive in tuberculosis-exposed individuals)
• Mitsuda reaction reflects the capacity for granuloma formation - specific for leprosy CMI status

BCG and Lepromin

• BCG vaccination can convert a lepromin-negative individual to positive by boosting CMI
• This forms the immunological basis for using BCG revaccination as immunoprophylaxis in household contacts of leprosy patients in endemic countries (e.g., Brazil's national program)

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Q1. Discuss Briefly Drug Resistance in Non-HIV Sexually Transmitted Infections [10 marks]

INTRODUCTION

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1. NEISSERIA GONORRHOEAE (Most Critical)

Historical Timeline of Resistance

Current Treatment Challenge

• Ceftriaxone 500 mg IM (single dose) is now the last reliable monotherapy
• CDC 2021 guidelines: Ceftriaxone 500 mg IM (or 1g if weight >150 kg) + doxycycline 100 mg BD x7 days (if chlamydia not excluded) as dual therapy
• Oral cephalosporins (cefixime) are no longer recommended as first-line due to reduced susceptibility
• Decreasing susceptibility to ceftriaxone has been reported in Japan, UK, Europe (strains FC428, A8806)
• If ceftriaxone-resistant: gentamicin 240 mg IM + azithromycin 2g orally (alternative dual regimen)
• Disseminated gonococcal infection (DGI): Ceftriaxone 1g IV/IM every 24 hours

Resistance Mechanisms

• Beta-lactamase production (penicillinase-producing N. gonorrhoeae - PPNG)
• Chromosomal mutations in penA (altered PBP 2), mtrR (efflux pump upregulation), porB (porin changes reducing drug entry), ponA
• Mosaic penA alleles = most important mechanism for cephalosporin resistance

Surveillance

• Gonococcal Isolate Surveillance Project (GISP) in USA
• GASP (Gonococcal Antimicrobial Susceptibility Programme) globally
• WHO's Enhanced Gonococcal International Surveillance (EGASP)

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2. MYCOPLASMA GENITALIUM

• Macrolide resistance (azithromycin): Mutations in 23S rRNA gene (A2058G, A2059G); resistance rates of 40-80% in some regions
• Fluoroquinolone resistance (moxifloxacin): Mutations in gyrA and parC genes; rising
• Treatment approach:
  • First line: Azithromycin 1g stat, followed by 500 mg daily x4 days (extended regimen)
  • Resistance-guided therapy: If macrolide-resistant → moxifloxacin 400 mg daily x7-10 days
  • Pristinamycin, minocycline, doxycycline: alternative options
• NAAT-based resistance detection (identifying 23S rRNA mutations) is increasingly available

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3. TRICHOMONAS VAGINALIS

• Metronidazole resistance: Reported in 2-5% of cases; involves decreased pyruvate-ferredoxin oxidoreductase (PFOR) activity and altered hydrogenosome function
• Clinical relevance: Metronidazole 2g single dose failure → repeat treatment with metronidazole 500 mg BD x7 days OR tinidazole 2g single dose (often effective when metronidazole fails)
• High-dose tinidazole regimens for refractory cases

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4. HAEMOPHILUS DUCREYI (Chancroid)

• Plasmid-mediated resistance to tetracyclines, sulfonamides, and ampicillin is well documented
• Chloramphenicol resistance also reported
• Current recommendations: Azithromycin 1g single dose OR ceftriaxone 250 mg IM single dose (both effective)
• Ciprofloxacin 500 mg BD x3 days is an alternative
• Resistance to azithromycin and ceftriaxone has not yet emerged significantly

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5. TREPONEMA PALLIDUM (Syphilis)

• Penicillin: T. pallidum has remained uniformly sensitive to penicillin for over 70 years - no acquired penicillin resistance has been documented
• Benzathine penicillin G remains treatment of choice for all stages
• Macrolide (azithromycin) resistance: Well-documented; mutations in 23S rRNA gene (A2058G, A2059G); azithromycin should NOT be used for syphilis in populations with high macrolide resistance (e.g., MSM in USA, Europe)
• Tetracycline and doxycycline remain effective alternatives in penicillin-allergic patients

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6. CHLAMYDIA TRACHOMATIS

• No clinically significant resistance to doxycycline or azithromycin has been established in C. trachomatis
• Isolated treatment failures with azithromycin have been reported but resistance is not confirmed
• Doxycycline 100 mg BD x7 days remains first-line

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PRINCIPLES FOR MANAGING DRUG-RESISTANT STIs

1. Culture and sensitivity testing before changing therapy
2. Use dual therapy wherever possible (gonorrhea)
3. Test of cure for all gonorrhea cases
4. Partner notification and treatment to prevent reinfection
5. Resistance surveillance programs (GISP, GASP)
6. Avoid monotherapy with antibiotics at risk of resistance
7. Identify and treat co-infections (gonorrhea + chlamydia)

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Q2. Discuss Effect of STD Management on HIV Transmission [10 marks]

BIOLOGICAL BASIS: STDs FACILITATE HIV TRANSMISSION

How STIs Increase HIV Susceptibility (HIV Acquisition)

1. Ulcerative STIs (syphilis, herpes, chancroid, LGV, donovanosis): Disruption of the epithelial barrier allows direct HIV entry; ulcers concentrate HIV-susceptible cells (CD4+ T cells, macrophages, Langerhans cells) at the site of infection
2. Inflammatory STIs (gonorrhea, chlamydia, trichomoniasis): Recruit activated CD4+ T lymphocytes and macrophages (the primary HIV target cells) to the genital mucosa; increase number of HIV target cells at the exposure site
3. Increased genital HIV shedding: In HIV-infected persons with concurrent STIs, HIV RNA in genital secretions increases significantly (2-5 fold increase in genital HIV viral load)
4. Disruption of mucosal IgA: Inflammatory STIs disrupt secretory IgA, a key component of mucosal immunity against HIV
5. TNF-alpha and IL-6 released during STI inflammation upregulate HIV replication in latently infected cells
6. Herpes simplex virus-2 (HSV-2): Among the most important cofactors - HSV-2 seropositive individuals have 2-4x higher risk of HIV acquisition; during HSV reactivation (even subclinical), HIV viral load in genital secretions increases substantially

Quantitative Impact

• Each STI episode increases the per-act probability of HIV transmission by 2-5 fold
• Genital ulcer disease increases HIV transmission risk by 50-300 times per coital act (compared to baseline)
• Population-attributable fraction: STIs account for approximately 40% of HIV transmission in sub-Saharan Africa

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EFFECT OF STD TREATMENT/CONTROL ON HIV TRANSMISSION

A. Mwanza Trial (Tanzania) - Landmark Evidence

• Community-randomized trial; improved STD treatment in 6 intervention communities vs. 6 control communities
• Result: 42% reduction in HIV incidence in communities receiving improved STD treatment
• Demonstrated that syndromic STD management at community level can reduce HIV transmission
• Mechanism: reduced genital inflammation and ulceration → reduced HIV shedding and susceptibility

B. Rakai Trial (Uganda) - Important Contradictory Evidence

• Mass treatment for STIs (single-dose regimens) in community cohorts
• Did NOT show reduction in HIV incidence despite effective STD treatment
• Explanation: High prevalence of HSV-2 (not amenable to bacterial STI treatment); different epidemic stage; high background HIV viral load

C. Lessons from the Trials

• HIV epidemic is early (low background HIV prevalence)
• STIs are predominantly bacterial and treatable (chancroid, gonorrhea, syphilis)
• STD treatment is syndromic and prompt (not delayed)
• The effect is less marked in mature HIV epidemics driven by HSV-2 (viral, not bacterial)

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STD-SPECIFIC IMPACTS ON HIV TRANSMISSION

1. Treatment of Genital Ulcer Disease (GUD)

• Chancroid, syphilis, LGV, donovanosis: All ulcerative STIs markedly increase HIV transmission
• Treating and curing GUD removes the portal of entry/exit for HIV
• In areas of high GUD prevalence, STD management has the greatest HIV prevention impact

2. Herpes Simplex Virus-2 (HSV-2) Suppression

• HSV-2 is the most common cause of GUD worldwide and the most important STI cofactor for HIV
• Daily valacyclovir suppressive therapy (500 mg BD) reduces genital HSV shedding by >90%
• HPTN 039 trial: Acyclovir suppression reduced HSV shedding but did NOT significantly reduce HIV acquisition in HSV-2/HIV-negative persons
• Partners in Prevention HSV/HIV trial: Acyclovir suppression in HIV+/HSV-2+ discordant couples reduced HSV-2 shedding but did not reduce HIV transmission to HIV-negative partners
• Implication: suppression of HSV reactivation alone is insufficient; HIV viral load must also be suppressed

3. Gonorrhea and Chlamydia Treatment

• Treating urethral gonorrhea and chlamydia in HIV-infected men reduces HIV RNA in seminal plasma by log 10 (10-fold)
• This directly reduces HIV infectivity during the treatment period
• Cohen et al.: Treating STIs in HIV+ men reduced genital HIV viral load significantly

4. Trichomoniasis Treatment

• Trichomoniasis significantly increases genital HIV viral load in HIV+ women
• Treatment with metronidazole reduces vaginal HIV RNA levels
• HPTN 035 trial sub-analysis: Trichomoniasis was associated with increased HIV acquisition; treatment may reduce this

5. ART as the Most Potent STD-HIV Interaction Tool

• HPTN 052 trial: Early ART initiation in HIV+ partners in discordant couples reduced HIV transmission by 96% (later updated: 93%)
• By suppressing plasma and genital HIV viral load to undetectable levels, ART eliminates almost all sexual HIV transmission - Undetectable = Untransmittable (U=U)
• Implication: while STD treatment helps, ART is the most powerful intervention

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SYNDROMIC STD MANAGEMENT AND HIV PREVENTION

• Reduces delay in treatment, thereby shortening the window of increased HIV susceptibility
• Most effective for genital ulcer syndrome (chancroid, syphilis) and urethral discharge syndrome
• Enables treatment at primary care level in resource-limited settings
• Core of national STI programs in sub-Saharan Africa and South Asia

Integrated STI/HIV Services

• Combining STI treatment with HIV testing and counseling at the same visit increases uptake
• PrEP (Pre-Exposure Prophylaxis) for HIV-negative high-risk individuals who attend STI clinics
• STI clinics are an ideal entry point for identifying HIV-infected persons for ART initiation

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CONCLUSION

1. Healing genital ulcers (removing portal of entry/exit)
2. Reducing mucosal inflammation (reducing HIV target cell recruitment)
3. Lowering genital HIV viral load in HIV+ individuals with STIs
4. Population-level reduction of STI prevalence reduces HIV epidemic potential

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Q3. Short Notes

(a) Prevention of Transmission of Genital Herpes [5 marks]

EPIDEMIOLOGY CONTEXT

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1. ANTIVIRAL SUPPRESSIVE THERAPY

• Valacyclovir 500 mg once daily (drug of choice for suppression): Reduces subclinical viral shedding by >90% and reduces risk of transmission to susceptible partner by ~50% (NEJM 2004 - Corey et al., Discordant couple trial)
• Acyclovir 400 mg BD is an alternative
• Suppressive therapy benefits:
  • Reduces frequency and severity of outbreaks
  • Reduces asymptomatic shedding
  • Reduces transmission risk (but does NOT eliminate it)
  • Improves quality of life and reduces psychological burden
• Indication: All patients with genital herpes who have a seronegative sexual partner should be counseled about suppressive therapy

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2. CONDOM USE

• Consistent correct condom use reduces HSV-2 transmission by ~50%
• Condoms are more effective in protecting women from men than vice versa (larger male genital surface area covered)
• Limitation: HSV can shed from areas not covered by condoms (perineum, inner thighs, buttocks)
• Combined condom use + suppressive therapy reduces transmission risk by approximately 75%

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3. ABSTINENCE DURING OUTBREAKS

• Patients must be educated to abstain from sexual contact during prodrome (tingling, burning) and active outbreaks (lesions, ulcers, crusting)
• Transmission risk is highest during symptomatic shedding
• However, 70% of HSV transmission occurs during asymptomatic shedding - patients must understand transmission can occur even without visible lesions

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4. PATIENT EDUCATION AND PARTNER NOTIFICATION

• Disclose HSV status to sexual partners before sexual contact (partner notification)
• Educate about asymptomatic shedding: most transmission occurs when the infected partner has no symptoms
• Shedding is most frequent in the first 12 months after primary infection
• Partners should be offered HSV serology testing (type-specific IgG: HerpeSelect) to determine their own status

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5. EPISODIC THERAPY (HARM REDUCTION)

• When suppressive therapy is not used: Valacyclovir 500 mg BD x3 days (episodic therapy) at the first sign of prodrome
• Reduces duration and severity of outbreak
• Reduces (but does not eliminate) transmission during that episode

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6. SCREENING AND TESTING

• Type-specific HSV-2 serology (HerpeSelect or Captia HSV-2 IgG) for high-risk individuals
• Testing in serodiscordant couples to determine susceptibility
• Routine antenatal screening: identifying HSV-2 seronegative pregnant women whose partners are HSV-positive → risk of primary infection in pregnancy (most dangerous)

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7. NEONATAL HERPES PREVENTION (Special Consideration)

• Cesarean section for women with active genital herpes lesions at time of delivery (prevents neonatal herpes - 30-50% mortality)
• Suppressive valacyclovir from 36 weeks gestation in women with recurrent genital herpes (reduces outbreak frequency at delivery, reduces need for C-section)
• Avoid invasive fetal monitoring (scalp electrodes) in HSV-positive mothers

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8. VACCINE (Current Status)

• No licensed prophylactic HSV vaccine exists currently
• Several candidates in trials: glycoprotein subunit vaccines (gD2, gB2), mRNA-based vaccines
• Therapeutic vaccines (reduce shedding in infected individuals) are also under investigation

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(b) Treponemal Tests in Syphilis [5 marks]

DEFINITION AND PRINCIPLE

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TYPES OF TREPONEMAL TESTS

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PERFORMANCE CHARACTERISTICS

• Treponemal tests are more sensitive than non-treponemal tests in primary and late syphilis
• Sensitivity is low in the first few weeks post-infection but reaches ~100% by 12 weeks

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KEY PROPERTIES

• Treponemal test results remain reactive for life in most patients, even after successful treatment
• Exception: 15-25% of patients treated during primary syphilis may revert to non-reactive within 2-3 years
• This means reactive treponemal tests cannot distinguish active from past/treated infection

• Unlike non-treponemal tests (VDRL/RPR titers fall 4-fold after successful treatment), treponemal test titers do NOT correlate with disease activity
• Never use treponemal tests to monitor treatment

• Traditional algorithm: Nontreponemal test first (VDRL/RPR) → if reactive, confirm with treponemal test
• Modern "Reverse Sequence Screening": Automated treponemal EIA/CLIA first → if reactive, confirm with RPR for activity assessment

• Treponemal tests have higher specificity than non-treponemal tests but rare false positives occur with:
  • Other spirochetal infections (Lyme disease, leptospirosis, yaws, pinta)
  • Autoimmune/connective tissue diseases (SLE, RA)
  • Narcotic addiction
  • HIV infection

• Maternal IgG treponemal antibodies cross the placenta and can cause a false-positive treponemal test in neonates (passive transfer)
• IgM-specific FTA-ABS (FTA-ABS 19S IgM) or TPHA-IgM is used to detect active congenital syphilis (maternal IgM does not cross the placenta)

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DIAGNOSTIC ALGORITHM

Suspected Syphilis
        ↓
  VDRL / RPR (non-treponemal, quantitative)
        ↓
   If REACTIVE → TPHA/FTA-ABS (confirmatory)
        ↓
   If both REACTIVE → SYPHILIS CONFIRMED
        ↓
   Treat → Repeat VDRL/RPR at 3, 6, 12 months
   (4-fold fall in titer = adequate treatment response)

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Q4. Short Notes

(a) Congenital Syphilis [5 marks]

DEFINITION AND TRANSMISSION

• Primary/Secondary syphilis: 70-100%
• Early latent syphilis: ~40%
• Late latent syphilis: ~10%
• 30-40% of infected pregnancies result in stillbirth or perinatal death
• Of surviving infected infants, two-thirds are asymptomatic at birth

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CLASSIFICATION

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EARLY CONGENITAL SYPHILIS (< 2 years)

• Fever, irritability, failure to thrive, hepatosplenomegaly (most common finding), lymphadenopathy

• "Snuffles" (syphilitic rhinitis): most characteristic early sign - profuse, blood-stained, mucopurulent nasal discharge; highly infectious
• Syphilitic pemphigus: bullous/vesicular eruption at birth, especially on palms and soles; bullae rupture → erosions; very infectious
• Maculopapular rash (copper-red, like secondary syphilis) appearing at 2+ weeks; affects palms and soles
• Condyloma lata (moist, flat-topped papules at mucocutaneous junctions)
• Mucous patches, oral fissures (radiating fissures around mouth, anus → rhagades)
• Dry, wrinkled skin with café-au-lait hue

• Osteochondritis and periostitis: painful; infant refuses to move affected limb → "pseudoparalysis of Parrot" (looks like paralysis but is pain-related)
• Most commonly affects long bones; visible on X-ray (periosteal reaction, "celery stalk" appearance)

• Neurosyphilis (meningitis, CSF VDRL positive)
• Hydrops fetalis (severe cases)
• Thrombocytopenia, hemolytic anemia, leukocytosis
• Nephrotic syndrome (glomerulonephritis)

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LATE CONGENITAL SYPHILIS (≥ 2 years)

1. Hutchinson's teeth: Peg-shaped, notched upper central incisors (permanent teeth); barrel-shaped with central notch; pathognomonic
2. Interstitial keratitis: Corneal vascularization causing photophobia, lacrimation, and blindness; onset 5-16 years
3. 8th nerve deafness: Sensorineural; often bilateral; progressive

• Saddle nose deformity (destruction of nasal septum cartilage)
• Saber shins (anterior bowing of tibia from chronic periostitis)
• Frontal bossing (Olympian brow)
• Higoumenakia sign: Thickening of the sternoclavicular portion of the clavicle
• Scaphoid (boat-shaped) scapula

• Clutton's joints: Bilateral painless hydroarthrosis of large joints (especially knees); joint effusion without bone destruction
• Juvenile general paresis, juvenile tabes dorsalis (rare)
• Mental retardation

• Rhagades: Perioral and perianal radiating scars from healed fissures
• Moon's (mulberry) molars: Multiple poorly developed cusps on first molars
• Corneal opacity (from healed interstitial keratitis)
• Snuffles scar: Atrophic rhinitis

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DIAGNOSIS

• Serology: Quantitative VDRL/RPR on infant serum (not cord blood)
• Treponemal IgM (FTA-ABS IgM, TPHA-IgM) - detects active infection
• Darkfield microscopy / PCR of nasal discharge, skin lesions
• X-ray long bones: Periosteal reaction, osteochondritis
• CSF: VDRL, cell count, protein (for neurosyphilis)

TREATMENT

• Aqueous crystalline penicillin G 100,000-150,000 units/kg/day IV divided every 12h (first 7 days) then every 8h for total 10 days (for proven/probable congenital syphilis)
• Alternative: Procaine penicillin G 50,000 units/kg IM once daily x10 days
• Follow-up: VDRL/RPR at 3, 6, 12 months (should become non-reactive by 6-12 months)

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(b) ART in Patients Suffering from TB [5 marks]

IMPORTANCE OF THE QUESTION

1. Drug-drug interactions between anti-TB drugs and ARVs
2. Timing of ART initiation relative to TB treatment
3. Immune Reconstitution Inflammatory Syndrome (IRIS)
4. Overlapping toxicities
5. High pill burden affecting adherence

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WHEN TO START ART IN HIV-TB CO-INFECTION

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WHICH ART REGIMEN TO USE

• Efavirenz is an NNRTI; its levels are reduced ~26% by rifampicin, but therapeutic levels are maintained at standard 600 mg dose
• No dose adjustment needed for efavirenz when used with rifampicin
• Proven effective and well-tolerated in landmark trials (SAPiT, CAMELIA, STRIDE)

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DRUG INTERACTIONS - KEY POINTS

• Use Efavirenz or Dolutegravir 50 mg BD

• Substitute rifampicin with Rifabutin 150 mg daily (weak CYP3A4 inducer)
• Can be used with boosted PIs (lopinavir/ritonavir, darunavir/ritonavir)

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IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (TB-IRIS)

• Occurs in 8-40% of HIV-TB co-infected patients starting ART
• Paradoxical TB-IRIS: Pre-existing TB worsens after ART initiation (new lymphadenopathy, worsening pulmonary infiltrates, new effusions)
• Unmasking TB-IRIS: Subclinical TB becomes apparent after immune recovery
• Risk factors: CD4 < 50, high HIV viral load, early ART initiation, disseminated TB
• Management: Continue both ART and TB treatment; prednisolone 1.5 mg/kg/day x2 weeks then taper for moderate-severe IRIS
• TB meningitis IRIS: requires careful corticosteroid management (dexamethasone)

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OVERLAPPING TOXICITIES (ADDITIONAL CHALLENGE)

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SUMMARY OF WHO RECOMMENDATIONS (2021)

1. All HIV/TB co-infected patients should receive both ART and anti-TB treatment
2. Preferred ART: TDF + 3TC (or FTC) + EFV 600 mg
3. ART timing: Within 2 weeks if CD4 <50; 2-8 weeks if CD4 50-200; can defer to 8 weeks if CD4 >200 (except TB meningitis)
4. Use dolutegravir 50 mg BD as an alternative to EFV with rifampicin
5. Pyridoxine (Vitamin B6) 25-50 mg/day with all INH-containing regimens

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Q5. Write Briefly About: (a) Relapse in Leprosy and (b) Reactivation in Leprosy [5 marks each]

(a) RELAPSE IN LEPROSY [5 marks]

DEFINITION

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CRITERIA FOR DIAGNOSIS OF RELAPSE

1. Patient has completed a full course of WHO MDT (6 months for PB; 12 months for MB)
2. Patient was declared RFT (Released From Treatment)
3. New active lesions appear after a silent period of at least 2 years after completing PB MDT or 5 years after MB MDT
4. Rising Bacterial Index (BI): BI increase of 2+ on log scale from post-treatment baseline
5. Rising Morphological Index (MI): Reappearance of solid (viable) bacilli in slit-skin smear (MI > 0%)
6. New histological activity: Active granulomatous changes on biopsy

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INCIDENCE

• Paucibacillary (PB) relapse: Very low; approximately 0.1-0.7% per year with current WHO MDT
• Multibacillary (MB) relapse: Approximately 0.06-0.5% per year with current WHO MDT
• Historically higher rates were seen with dapsone monotherapy (5-25% in MB cases)
• WHO MDT dramatically reduced relapse rates

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CAUSES OF RELAPSE

1. Persistent viable organisms ("persisters"): M. leprae can remain viable but metabolically dormant within Schwann cells and macrophages even after completing MDT; if immune defenses wane, these persisters multiply
2. Drug resistance: Especially dapsone and rifampicin resistance; rising concern
3. Inadequate treatment: Subtherapeutic doses, interrupted treatment, incorrectly classified as PB when actually MB
4. Re-infection: Especially in highly endemic areas (considered the most common cause of "relapse" in some studies)

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DISTINGUISHING RELAPSE FROM LATE TYPE 1 REACTION

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MANAGEMENT OF RELAPSE

• Confirm relapse: BI, MI, biopsy; drug susceptibility testing where possible
• Re-treat with a full course of WHO MDT:
  • PB relapse → MB MDT for 12 months (upgrade to MB regardless of current classification)
  • MB relapse → Repeat 12-month MB MDT
• If dapsone resistance: Replace dapsone with clofazimine
• If rifampicin resistance: Use intensive regimen: ofloxacin 400 mg + minocycline 100 mg + clofazimine 50 mg daily for 24 months
• Investigate household contacts

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(b) REACTIVATION IN LEPROSY [5 marks]

DEFINITION

• During MDT (if immunity wanes)
• In partially treated patients
• In individuals with subclinical infection who develop immunosuppression

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DISTINCTION FROM RELAPSE

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CIRCUMSTANCES LEADING TO REACTIVATION

• HIV co-infection: While leprosy is not an AIDS-defining illness and HIV does not dramatically alter leprosy course, advanced immunosuppression (very low CD4) can unmask or reactivate subclinical leprosy
• IRIS (Immune Reconstitution Inflammatory Syndrome): Paradoxically, starting HAART in HIV-leprosy co-infected patients can precipitate an acute Type 1 reaction as CMI is restored (see "unmasking IRIS")
• Organ transplantation: Post-transplant immunosuppression (calcineurin inhibitors, steroids) has been associated with leprosy reactivation; multibacillary forms predominate
• Biological therapies: Anti-TNF agents (infliximab, adalimumab) can potentially reactivate dormant mycobacterial infections including leprosy
• Corticosteroid therapy for other conditions

• Pregnancy suppresses CMI → leprosy can reactivate or worsen during pregnancy and the puerperium
• Hormonal and immunological changes of pregnancy lower CMI → dormant bacilli multiply
• Postpartum recovery of CMI can trigger Type 1 reactions

• Nutritional deficiencies, febrile illness, trauma, and physical stress can impair cell-mediated immunity sufficiently to allow reactivation
• Relevant in endemic, resource-poor settings

• M. leprae can exist in a metabolically dormant state within Schwann cells and macrophages
• These persisters are not killed by standard MDT (which targets actively replicating organisms)
• When host immunity is compromised, persisters resume replication
• Generation time of M. leprae is 12-14 days; reactivation is therefore slow (months to years)

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CLINICAL FEATURES OF REACTIVATION

• New erythematous, infiltrated skin lesions (similar to Type 1 reaction)
• New areas of sensory loss or motor weakness
• Nerve tenderness
• Rising BI/MI on slit-skin smear
• Histology: Active granulomatous inflammation; bacilli on Fite-Faraco stain
• May be associated with a reaction (Type 1 in borderline; Type 2 in LL)

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MANAGEMENT

1. Restart/complete MDT (appropriate regimen for leprosy type)
2. Treat the immunosuppressive cause:
   • Manage HAART-related IRIS with prednisolone
   • Adjust immunosuppressive regimens in transplant patients where possible
   • Nutritional support
3. Treat concurrent lepra reaction (if present) with prednisolone
4. Surveillance: Monitor BI and MI during treatment to confirm response
5. Contact tracing in households

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Q6. Discuss 'Pure Neuritic Leprosy' [10 marks]

DEFINITION

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EPIDEMIOLOGY

• Accounts for 4-8% of all leprosy cases globally
• In India (especially West Bengal, Andhra Pradesh): may account for up to 17% of all leprosy cases - the highest proportion worldwide
• Also relatively common in Nepal (5-10% of cases)
• Both paucibacillary and multibacillary forms exist
• According to WHO classification, any patient with pure nerve involvement (without skin lesions) is classified as multibacillary for treatment purposes

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PATHOGENESIS

• M. leprae invades peripheral nerve trunks without seeding the dermis from the outset
• The organism enters Schwann cells via the PGL-1 - laminin-2 - alpha-dystroglycan receptor axis
• Predilection for cooler, superficial, anatomically vulnerable nerve trunks (sites of entrapment)
• Granulomatous inflammation within the nerve epineurium and endoneurium leads to:
  • Demyelination
  • Axonal destruction
  • Nerve trunk enlargement (fusiform thickening)
  • Progressive sensory, motor, and autonomic loss
• Up to 35% of PNL patients eventually develop skin lesions over follow-up, suggesting neuritic involvement often precedes the cutaneous phase of leprosy

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CLINICAL FEATURES

Nerve Trunks Commonly Involved

Symptoms and Signs

• Hypoesthesia or anesthesia in the nerve's territory
• Paresthesia, dysesthesia (early)
• Loss of pain and temperature → risk of trophic ulcer
• No skin patch corresponding to sensory loss (distinguishes from typical leprosy)

• Muscle weakness and wasting in affected nerve territory
• Claw hand, wrist drop, foot drop depending on nerve

• Anhidrosis in affected nerve territory
• Dry, fissured skin

• Thickened, firm, fusiform, nodular or beaded nerve trunk (the key clinical sign)
• May or may not be tender
• Enlargement is often asymmetric

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DIAGNOSIS

Clinical Diagnosis

• Thickened peripheral nerve + sensory loss in its territory + no skin lesions

WHO Diagnostic Criteria for Leprosy

1. Hypopigmented patch with anesthesia
2. Thickened/enlarged peripheral nerve with loss of sensation ± weakness of supplied muscles ✓
3. Acid-fast bacilli on slit-skin smear

Investigations

• May show AFB in up to 16% of PNL cases (from standard smear sites)
• If SSS is positive for AFB → not PNL by definition (suggests subclinical skin involvement)

• Preferred nerve: Radial cutaneous nerve at wrist or sural nerve (sensory nerves preferred to avoid adding motor deficit)
• Findings: Granulomatous inflammation within nerve, acid-fast bacilli (Fite-Faraco stain), Schwann cell destruction
• AFB may be demonstrated in 16% of cases; PCR positive in ~50% of cases

• Less invasive than biopsy; combined with multiplex PCR → improved sensitivity and specificity

• Sensitivity 34-80% in PB forms; >90% in MB forms
• 16S rRNA reverse-transcription PCR can assess M. leprae viability

• Reduced nerve conduction velocity, prolonged latencies
• Helps determine extent and severity of nerve damage
• Monitors progression vs. recovery

• High-resolution ultrasound: thickened, hypoechoic nerve cross-sectional area
• Fusiform enlargement at sites of entrapment
• Non-invasive; useful in field settings; can follow multiple nerves

• IgM anti-phenolic glycolipid-1 antibody elevated in multibacillary forms
• Can support diagnosis when serology is positive in a patient with nerve thickening

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DIFFERENTIAL DIAGNOSIS

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TREATMENT

• Classify as multibacillary (WHO 2018 guidelines): Any patient with nerve involvement without skin lesions = multibacillary
• WHO MB-MDT for 12 months:
  • Rifampicin 600 mg once monthly (supervised)
  • Clofazimine 300 mg once monthly + 50 mg daily
  • Dapsone 100 mg daily
• Treat concurrent neuritis/reaction with prednisolone (1-2 mg/kg/day tapered over 20 weeks)
• Physiotherapy: Joint mobilization, splinting, muscle-strengthening
• Surgical nerve decompression: Indicated for persistent, refractory neuritis with risk of permanent paralysis

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PROGNOSIS

• Better if detected early (before permanent nerve fiber loss)
• Nerve function may improve with MDT + steroid treatment if diagnosis is timely
• Delayed diagnosis → permanent disability (claw hand, foot drop, trophic ulcer)
• Up to one-third develop skin lesions during follow-up - must be monitored

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Q7. Write About 'Newer Drugs to Treat Leprosy' [10 marks]

CONTEXT

1. Drug-resistant leprosy (especially rifampicin-resistant cases)
2. Patients intolerant to standard MDT drugs
3. Alternative shorter regimens
4. Single-lesion PB leprosy (ROM regimen)
5. Post-exposure prophylaxis

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1. FLUOROQUINOLONES

Ofloxacin

• Mechanism: Inhibits DNA gyrase (topoisomerase II) → prevents DNA replication
• Activity against M. leprae: Bactericidal; 99.99% killing of M. leprae after single dose
• Dose: 400 mg daily
• Clinical use:
  • ROM regimen (Rifampicin-Ofloxacin-Minocycline): Single dose for single-lesion PB leprosy
  • Alternative to dapsone in MDT-intolerant patients
  • Second-line drug for rifampicin-resistant leprosy
• Resistance: Mutations in gyrA and parC genes; if ofloxacin-resistant, no fluoroquinolone should be used

Moxifloxacin

• Most potent fluoroquinolone against M. leprae; superior to ofloxacin in minimum bactericidal concentration
• Dose: 400 mg daily
• Clinical use:
  • Rifampicin-resistant leprosy regimens
  • Proposed component of newer intensive MDT protocols
  • Activity retained when ofloxacin-resistant

Levofloxacin

• Dose: 500 mg daily
• Second-line option; similar mechanism to ofloxacin

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2. MINOCYCLINE

• Class: Second-generation tetracycline
• Mechanism: Inhibits 30S ribosomal subunit → protein synthesis inhibition; also has anti-inflammatory and immunomodulatory properties
• Activity: Bactericidal against M. leprae in mouse footpad models; kills >99% organisms after multiple doses
• Dose: 100 mg daily
• Clinical uses:
  • ROM regimen: Single dose (100 mg) for single-lesion PB leprosy
  • Replacement for dapsone in intolerant patients
  • Second-line treatment for rifampicin-resistant leprosy
• Advantages: Good tissue penetration, including nerve tissue; unique among tetracyclines in significant anti-mycobacterial activity
• Side effects: Dizziness, photosensitivity, blue-gray skin pigmentation with prolonged use, esophageal ulcers

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3. CLARITHROMYCIN

• Class: Macrolide antibiotic
• Mechanism: Inhibits 50S ribosomal subunit → protein synthesis inhibition
• Activity: Bactericidal against M. leprae; effective in mouse footpad studies
• Dose: 500 mg daily
• Clinical uses:
  • Rifampicin-resistant leprosy (as part of second-line regimen)
  • Alternative combination regimens in intolerant patients
  • Intensive regimen for MB leprosy with high bacterial load: Rifapentine 900 mg + moxifloxacin 400 mg + clarithromycin 1000 mg once monthly x12 months
• Side effects: GI upset, metallic taste, hepatotoxicity (rare)

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4. RIFAPENTINE (Long-acting Rifamycin)

• Class: Long-acting rifamycin derivative
• Mechanism: Inhibits RNA polymerase (same target as rifampicin)
• Activity: Half-life ~15-18 hours (vs. rifampicin ~2-4 hours) → can be given once weekly or once monthly
• Dose: 900 mg once monthly (in proposed intensive regimen)
• Advantage over rifampicin: Higher Cmax (peak concentration), longer half-life → potentially superior bactericidal activity; less likely to develop resistance
• Clinical use: Proposed as substitute for rifampicin in intensive regimens for highly infected MB patients; more effective than rifampicin in combination studies
• Side effect profile: Similar to rifampicin (hepatotoxicity, flu-like syndrome, CYP3A4 induction)

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5. ROM REGIMEN (Single-Dose Combination for Single-Lesion PB Leprosy)

• WHO-endorsed for single skin-lesion paucibacillary leprosy (alternative to 6-month PB-MDT)
• Efficacy comparable to 6-month standard PB-MDT in field studies
• Advantage: Single dose = 100% compliance; suitable for resource-limited, high-endemic settings
• Limitation: Not suitable for multi-lesion PB or any MB disease

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6. PROPOSED NEWER INTENSIVE REGIMENS (For High Bacterial Load / Rifampicin-Resistant MB)

Rifampicin-Sensitive MB with High Bacterial Load

• Rifapentine 900 mg + Moxifloxacin 400 mg + Clarithromycin 1000 mg (or minocycline 200 mg) - all once monthly for 12 months

Rifampicin-Resistant Leprosy

• Moxifloxacin 400 mg + Clofazimine 50 mg + Clarithromycin 500 mg + Minocycline 100 mg - all daily (supervised)

• Moxifloxacin 400 mg + Clarithromycin 1000 mg + Minocycline 200 mg - all once monthly

• Intensive 6 months: Clarithromycin + Minocycline + Clofazimine daily
• Continuation 18 months: Clofazimine + clarithromycin OR minocycline monthly

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7. IMMUNOTHERAPY - M. INDICUS PRANII (Mw Vaccine)

• Mycobacterium indicus pranii (formerly called Mycobacterium w or Mw): rapidly growing, non-pathogenic, cultivable mycobacterium sharing several antigens with M. leprae
• Administration: Killed vaccine, 0.1 mL intradermally in two equally divided doses on both arms; repeated every 3-6 months until end of MDT treatment
• Mechanism: Augments cell-mediated immunity against M. leprae; converts lepromin-negative patients toward positivity
• Benefits in clinical trials:
  • More rapid bacterial clearance (faster fall in BI and MI)
  • Earlier smear negativity
  • More rapid histological clearance of skin lesions
• Particularly useful in highly infected (BI 4+, 5+, 6+) MB patients where standard MDT alone leads to slow smear conversion
• Approved and used in India as adjunct immunotherapy

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8. TOPICAL INSULIN

• Novel use: Topical insulin dressings have been shown to promote healing of trophic (neuropathic) plantar ulcers in leprosy patients
• Mechanism: Insulin promotes keratinocyte proliferation and wound healing via IGF-1 receptors
• Considered a newer therapeutic tool in leprosy rehabilitation (not antimicrobial but adjunct wound care)

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SUMMARY TABLE: Newer Drugs in Leprosy

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Q8. Elaborate on Management of: (a) Plantar Ulcers and (b) Lagophthalmos in Leprosy [10 marks]

(a) Management of Plantar Ulcers in Leprosy [5 marks]

PATHOPHYSIOLOGY (Brief Recap)

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PRINCIPLES OF MANAGEMENT

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PHASE 1: ACTIVE ULCER MANAGEMENT

A. Offloading (Most Critical)

• Complete bed rest until the ulcer heals (non-negotiable)
• Total Contact Cast (TCC): Gold standard offloading device
  • Custom-molded plaster cast that distributes plantar pressure evenly across the entire sole
  • Reduces peak plantar pressure by 84-92%
  • Changed every 1-2 weeks; continued until full healing
• Prefabricated removable cast walkers (RCW): Alternative when TCC expertise unavailable
• Crutches, wheelchair for mobilization during active ulceration

B. Wound Care

• Daily soaking in warm clean water + mild soap (10-15 minutes): softens and helps remove callus and debris
• Debridement of callus rim: Using scalpel/curette under aseptic conditions; thick callus must be removed as it concentrates plantar pressure and prevents healing
• Removal of necrotic/sloughy tissue: Debridement at each dressing change
• Antiseptic dressings: Povidone-iodine, silver sulfadiazine cream
• Topical insulin dressings: Evidence-based; promotes wound healing via IGF-1 receptor stimulation on keratinocytes
• Moist wound dressings (hydrogel, hydrocolloid, alginate): For clean granulating wounds; maintains moist wound environment
• Dressings changed daily (or as needed)

C. Antibiotics

• Infected ulcers: Culture-directed systemic antibiotics
• Empirical regimen (mild-moderate infection): Amoxicillin-clavulanate 625 mg BD OR ciprofloxacin 500 mg BD
• Osteomyelitis: IV antibiotics for 4-6 weeks (based on culture: anti-staphylococcal, coverage for Gram-negatives and anaerobes)
• Signs of osteomyelitis: probing to bone, sinus tract, X-ray changes (periosteal reaction, osteolysis, sequestrum)

D. MDT for Underlying Leprosy

• Continue or initiate MDT to halt further nerve damage
• Treat concurrent lepra reactions (prednisolone)

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PHASE 2: LONG-TERM PREVENTION

A. Custom Therapeutic Footwear

• Microcellular rubber (MCR) footwear: Standard leprosy rehabilitation footwear; soft, shock-absorbing MCR sole redistributes plantar pressure away from pressure points
• Rocker-bottom sole: For foot drop (removes toe-off requirement during walking)
• Toe box spacers/caps: For claw toes preventing tip pressure
• Footwear must be worn at all times - even indoors (barefoot walking prohibited)
• Regular footwear inspection for foreign bodies (patient cannot feel sharp objects)

B. Patient Self-Care Education

• Daily foot inspection using a mirror for plantar surface
• Report any redness, warmth, blistering, or new wound immediately
• Never walk barefoot
• Daily moisturizing with petroleum jelly or coconut oil to prevent fissures
• Regular callus trimming at clinic (every 2-4 weeks)
• Proper sock use (protects from friction)

C. Physiotherapy

• Active and passive joint mobilization exercises: prevents contractures
• Strengthening exercises for residual muscle function
• Gait retraining

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PHASE 3: SURGICAL MANAGEMENT

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(b) Management of Lagophthalmos in Leprosy [5 marks]

DEFINITION AND MECHANISM

• Corneal exposure → evaporative drying → exposure keratopathy
• Failure of tear distribution → punctate corneal epithelial erosions
• Corneal ulceration → secondary bacterial infection → corneal opacity/perforation → blindness
• Risk is compounded by concurrent corneal anesthesia (trigeminal nerve involvement) - the patient cannot feel corneal pain, so corneal injury goes unnoticed

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GRADING OF LAGOPHTHALMOS

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MANAGEMENT BY LEVEL

A. Medical/Conservative Management

• Artificial tear drops (lubricating eye drops): e.g., methylcellulose 0.5% or carboxymethylcellulose 0.5% - 4-6 times daily; prevents corneal drying
• Lubricating eye ointment (liquid paraffin): Applied at night before sleep; prevents nocturnal corneal exposure
• Protective spectacles: Side-shielded glasses during the day to reduce wind/dust exposure
• Moisture chamber goggles: For severe cases with Grade 2-3 lagophthalmos
• Lateral taping of eyelids at night: Simple, effective method to achieve lid closure during sleep

• MDT: Continue to prevent further nerve damage
• Prednisolone for active facial neuritis: If acute neuritis causing fresh lagophthalmos → prednisolone 40 mg/day with taper may partially or fully recover nerve function if started early (within weeks of onset)
• Eye toilet: Regular cleaning of lids with clean cotton and boiled water if secretions accumulate

• Patient trained to perform "Blinking exercises": Forced voluntary blink every few minutes
• "Bell's phenomenon" awareness: Eyeball rolls upward when eye closed - protective, but incomplete
• Report red eye, photophobia, or any change in vision immediately
• Regular eye examination every 6 months in all MB leprosy patients

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B. Surgical Management

• Lateral tarsorrhaphy: Suturing of lateral eyelid margins together, reducing palpebral fissure width
• Simple, quick; can be done under local anesthesia
• Useful bridge procedure until nerve recovery is assessed or while awaiting definitive surgery
• Reduces corneal exposure without permanently affecting cosmesis or vision

• For irreversible facial palsy with significant lagophthalmos
• More permanent reduction of palpebral aperture
• Trade-off between protection and cosmetic appearance/field of vision

• Gold weight implantation in the upper eyelid: A small gold weight (0.8-1.6g) implanted in the upper lid adds gravitational force to assist lid closure
• Works by gravity (patient upright/ambulatory)
• Does not help during sleep (patient recumbent) - still needs night ointment
• Considered gold standard for unilateral facial palsy with lagophthalmos

• Stainless steel spring implanted in upper lid: provides active closure force regardless of position
• More technically demanding than gold weight

• Connects the upper lid to the frontalis muscle
• Useful when voluntary blinking/eye closure is completely lost
• Requires donor fascia (thigh)

• Cross-facial nerve grafts: rare; for young patients with complete facial nerve palsy

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MONITORING

• Visual acuity testing at every visit
• Corneal sensation testing (wisp of cotton) - if both lagophthalmos + corneal anesthesia = very high-risk
• Slit-lamp examination for early keratopathy
• Schirmer's test for tear production assessment

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Q9. Discuss Differential Diagnosis of Flat and Hypopigmented Lesion in Leprosy [10 marks]

INTRODUCTION

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FEATURES OF A LEPROSY PATCH TO REMEMBER

• Hypopigmented (or erythematous on dark skin)
• Poorly defined (indeterminate, LL) or well-defined (TT, BT)
• Anesthetic or hypoesthetic (reduced sensation to touch/pain/temperature within the patch)
• Anhidrotic (dry center; no sweating within the patch)
• May show associated nerve thickening
• Hair over the patch may be lost (madarosis within the patch)

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DIFFERENTIAL DIAGNOSES

1. PITYRIASIS ALBA

• Most common mimic of indeterminate leprosy
• Common in children on face, upper arms, trunk
• Hypopigmented, poorly defined macules with fine surface scaling
• Sensation fully intact (normal touch, pain, temperature sensation) - key distinguishing point
• No nerve thickening
• Associated with atopic tendency and sun exposure
• Treatment: emollients, mild topical steroids, sunscreen; self-limiting

2. PITYRIASIS VERSICOLOR (Tinea Versicolor)

• Caused by Malassezia furfur/globosa
• Multiple, well-defined, finely scaly hypopigmented or hyperpigmented macules
• Distribution: trunk, upper arms, neck
• Sensation intact
• Positive KOH examination: Spaghetti and meatball appearance (short hyphae + spores)
• Wood's lamp: Golden-yellow fluorescence
• Treatment: topical/oral antifungals

3. VITILIGO

• Autoimmune melanocyte destruction
• Completely depigmented (chalk-white), not just hypopigmented - milk-white with complete loss of melanin
• Well-defined, sharp margins (vs. poorly defined in indeterminate leprosy)
• Sensation completely normal - no anesthesia
• No nerve thickening
• Wood's lamp: brilliant white fluorescence (not seen in leprosy)
• Associated autoimmune conditions (thyroid disease, DM)
• Bilateral symmetric distribution common

4. NEVUS DEPIGMENTOSUS (Achromic Nevus)

• Congenital, stable, unilateral hypopigmented macule/patch
• Present from birth or early childhood; does not progress
• Normal sensation
• No associated nerve thickening
• Wood's lamp: accentuates but does not produce chalk-white (unlike vitiligo)

5. TINEA CORPORIS (Ringworm)

• Dermatophyte infection
• Annular, scaly, erythematous ring with active advancing edge and central clearing
• Sensation intact
• May mimic borderline leprosy (annular lesions)
• KOH: fungal hyphae
• Responds to antifungals
• Leprosy: annular lesions with "punched-out" or irregular edges, central anesthesia, nerve thickening

6. SEBORRHOEIC DERMATITIS

• Greasy, scaly, erythematous patches on seborrheic areas (scalp, face - nasolabial folds, eyebrows, chest)
• Sensation intact
• Associated dandruff
• Responds to antifungals (ketoconazole) and topical steroids

7. DISCOID LUPUS ERYTHEMATOSUS (DLE)

• Erythematous plaques with central scarring, atrophy, follicular plugging, scales
• Photodistribution (face, scalp, ears)
• Sensation intact in the lesions
• ANA, anti-dsDNA, histology (interface dermatitis) - differentiate
• No nerve thickening

8. SARCOIDOSIS

• Papular, nodular, or plaque lesions; may be hypopigmented
• Mimics borderline leprosy
• Non-caseating granulomas on biopsy (no AFB; langhans giant cells without necrosis)
• Elevated serum ACE, bilateral hilar lymphadenopathy on CXR
• No nerve thickening (though sarcoidosis can rarely affect nerves)

9. POST-INFLAMMATORY HYPOPIGMENTATION

• Follows any inflammatory dermatosis (eczema, psoriasis, etc.)
• History of prior skin disease at the same site
• Sensation intact
• No active inflammation, no nerve thickening

10. LICHEN SCLEROSUS (if trunk/genitals)

• Ivory-white, atrophic plaques with wrinkled ("cigarette paper") texture
• Telangiectasias, purpura, follicular plugging
• Genital involvement common
• Sensation may be altered (but different mechanism: fibrosis)
• Biopsy: epidermal atrophy, homogenization of upper dermis, no granulomas

11. MORPHOEA (Localized Scleroderma)

• Ivory/lilac-colored, indurated plaque with violaceous halo
• Sensation altered due to fibrosis - may superficially mimic leprosy
• Biopsy: fibrosis of dermis, no granulomas, no AFB
• No nerve thickening

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SUMMARY TABLE: Key Differentiating Features

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CLINICAL APPROACH TO CONFIRM/EXCLUDE LEPROSY

1. Test sensation within the patch (fine touch, pin-prick, temperature)
2. Palpate peripheral nerve trunks (ulnar, radial cutaneous, greater auricular, posterior tibial)
3. Slit-skin smear (SSS) for AFB from lesion edge, earlobes, forehead
4. Skin biopsy from active edge (Fite-Faraco stain for AFB; histopathology for granulomas)
5. PCR for M. leprae if equivocal histology
6. Lepromin test (prognostic; not diagnostic)

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Q10. Short Notes [5 marks each]

(a) Uncommon Presentations of Multibacillary Leprosy [5 marks]

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1. HISTOID LEPROSY (Wade's Histoid Leprosy)

• Smooth, shiny, dome-shaped, hemispherical nodules on otherwise normal skin
• Located on face, back, buttocks, over bony prominences (elbows, knees)
• Arises in patients on dapsone monotherapy (dapsone resistance context) or de novo
• Histopathology: Predominance of spindle-shaped histiocytic cells in storiform pattern; very high AFB load
• Mimics dermatofibroma, neurofibroma, xanthoma
• Clinical significance: High bacillary reservoir; requires aggressive MDT

2. DIFFUSE LEPROMATOUS LEPROSY (Lucio Leprosy)

• Diffuse non-nodular skin infiltration → waxy, shiny skin ("lepra bonita")
• Loss of all body hair (complete madarosis)
• No discrete nodules (unlike classic LL)
• Associated with Lucio phenomenon (purpuric ascending ulcers)
• Endemic in Mexico, Costa Rica; M. lepromatosis

3. PURE NEURITIC (PRIMARY NEURITIC) LEPROSY

• Peripheral nerve involvement without any skin lesions
• 5-17% of leprosy in India
• Nerve biopsy for diagnosis; classified as MB

4. SLE-LIKE (LUPUS-LIKE) PRESENTATION

• False-positive VDRL, antiphospholipid antibodies, lupus anticoagulant
• Fusiform fingers, swan neck deformity, hypergammaglobulinemia, anemia
• Can be severely misdiagnosed as SLE → immunosuppressants given → catastrophic

5. FIRST PRESENTATION AS ENL (TYPE 2 REACTION)

• ENL with fever, subcutaneous nodules, systemic illness as the presenting feature before skin patches are appreciated
• Mistaken for panniculitis, lymphoma, vasculitis, or sepsis

6. LEPROSY-IRIS (POST-HAART UNMASKING)

• In HIV-leprosy co-infection, HAART initiation restores immunity → sudden Type 1 or Type 2 reaction
• May unmask previously undiagnosed MB leprosy in an HIV-infected patient
• Presents as acute inflammatory skin and nerve disease after HAART initiation

7. LEPROSY IN ORGAN TRANSPLANT RECIPIENTS

• Post-transplant immunosuppression unmasks latent infection
• MB forms predominate in transplant patients
• May present atypically; should be considered in skin manifestations of transplant patients in endemic areas

8. LEPROSY PRESENTING AS PERIPHERAL NEUROPATHY MIMICKING VASCULITIC NEUROPATHY

• Mononeuritis multiplex pattern in MB leprosy during ENL (immune-complex vasculitic neuritis)
• Multiple asymmetric nerve deficits can mimic ANCA-associated vasculitic neuropathy
• Nerve biopsy and AFB staining clarify diagnosis

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(b) Bacteriological Index in Leprosy [5 marks]

DEFINITION

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RIDLEY'S LOGARITHMIC SCALE

• When BI = 1+ or 2+: examine at least 100 oil-immersion fields
• When BI = 3+, 4+, 5+, 6+: examine at least 25 oil-immersion fields

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PROCEDURE

• Standard sites: Both earlobes, forehead (glabella), chin
• Additional: Active lesion (active edge), nasal mucosa

1. Cleanse site with spirit swab; allow to dry
2. Pinch skin firmly between thumb and index finger (blanches skin, reduces bleeding)
3. Make a 5 mm incision with a sterile scalpel blade to dermis depth
4. Scrape the cut edge with the blade to obtain tissue fluid and cells (not blood)
5. Spread material on a glass slide in a circular smear (~5 mm diameter)
6. Fix in heat; stain by Ziehl-Neelsen or Fite-Faraco method
7. Examine under oil immersion (1000x)

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CALCULATING THE PATIENT'S BI

• Right earlobe: 5+, Left earlobe: 5+
• Forehead: 4+, Chin: 4+

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CORRELATION WITH LEPROSY SPECTRUM

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CLINICAL APPLICATIONS OF BI

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LIMITATIONS OF BI

1. Falls slowly after treatment (dead bacilli persist; BI may remain elevated 3-5 years post-MDT)
2. Does not distinguish viable from dead bacilli → must be combined with Morphological Index (MI) for assessment of treatment response
3. Inter-observer variability in smear preparation and reading
4. Not routinely used in WHO field programs for treatment decisions (WHO uses lesion count)
5. Requires trained laboratory personnel

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BI vs. MI - KEY COMPARISON

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