Leprosy: Classification & Diagnosis

Leprosy (Hansen's disease) is a chronic granulomatous infection by Mycobacterium leprae that selectively targets skin and peripheral nerves. The clinical spectrum is determined entirely by the host's cell-mediated immunity (CMI) — strong CMI gives paucibacillary tuberculoid disease, weak CMI gives multibacillary lepromatous disease. This single immunological axis explains the Ridley-Jopling spectrum, the smear results, the lepromin test, and the WHO treatment categories, so mastering it answers most NEET PG questions.

The organism and basics

• Causative agent: Mycobacterium leprae (Hansen's bacillus, discovered by Armauer Hansen, 1873 — the first bacterium identified as a cause of human disease). A second species, M. lepromatosis, causes diffuse lepromatous leprosy / Lucio phenomenon (Mexico, Caribbean).
• Acid-fast, obligate intracellular, gram-positive, cannot be cultured in vitro (a favourite fact).
• Generation time ~12-14 days — the slowest-growing known human pathogen; explains the long incubation (average 3-5 years, range months to 20+ years).
• Optimal growth temperature ~27-30°C → predilection for cooler body parts: skin, superficial peripheral nerves, anterior chamber of eye, testes, nasal mucosa. Spares warm areas (axilla, groin, perineum, scalp vertex, midline of back).
• Animal models: mouse footpad (Shepard) and the nine-banded armadillo (natural reservoir; allows large bacillary yields).
• Transmission: mainly nasal droplets/respiratory secretions from untreated MB cases; skin-to-skin is minor. Most exposed people are naturally resistant.

High-yield: M. leprae is the only mycobacterium that invades peripheral nerves (Schwann cells) via binding to the G-domain of laminin-2 in the basal lamina, using PGL-1 (phenolic glycolipid-1) and the host receptor α-dystroglycan.

Classification systems

Two systems run in parallel and are heavily tested. The Ridley-Jopling (1966) classification is research/immunological; the WHO classification is operational/treatment-based.

Ridley-Jopling spectrum (TT → BT → BB → BL → LL)

Based on five parameters: clinical features, bacteriological index, lepromin test, histopathology, and immunology. The spectrum moves from high CMI (tuberculoid pole) to low CMI (lepromatous pole).

Feature	TT (Tuberculoid)	BT	BB (Mid-borderline)	BL	LL (Lepromatous)
Number of lesions	Single / very few (1-3)	Few (up to ~10)	Several	Many	Numerous, symmetrical, innumerable
Symmetry	Asymmetric	Asymmetric	—	Tends symmetric	Strikingly symmetric
Lesion morphology	Well-defined plaque, raised dry margin, hypopigmented, anhidrotic, hairless	Like TT + satellite lesions	"Punched-out"/inverted-saucer annular lesions	Shiny papules/nodules, ill-defined	Diffuse infiltration, nodules, "leonine facies", madarosis
Sensation in lesion	Markedly anaesthetic	Anaesthetic	Reduced	Slightly reduced	Late/minimal loss in lesions (diffuse glove-and-stocking later)
Nerve involvement	Early, single thick nerve, asymmetric	Asymmetric, may be severe	—	Many nerves	Late, symmetric, "stocking-glove"
Bacteriological index (BI)	0	0-1+	2-3+	4-5+	5-6+ (globi, foamy Virchow cells)
Lepromin (Mitsuda) test	Strongly positive (+++)	Weakly positive	Negative	Negative	Negative
Histology	Epithelioid granuloma + Langhans giant cells, nerve destroyed, no bacilli	Epithelioid granuloma, fewer lymphocytes	Diffuse epithelioid, no giant cells	Macrophages + some lymphocytes	Foamy (Virchow/lepra) cells, Grenz zone, abundant bacilli/globi
Immunity (CMI)	High	—	Lowest stability	—	Absent (Th2 dominant)

High-yield: The Th1 (tuberculoid) pole shows IL-2, IFN-γ, IL-12 and strong CMI; the Th2 (lepromatous) pole shows IL-4, IL-5, IL-10 with high antibody but useless humoral response. BB (mid-borderline) is the most immunologically unstable and rarely seen as it quickly downgrades or upgrades.

Two special variants sit outside the main spectrum:

• Indeterminate leprosy (I): earliest detectable form — a single ill-defined hypopigmented macule with minimal sensory loss; may heal spontaneously or evolve into any spectrum form.
• Pure neuritic leprosy (PNL): nerve involvement without skin lesions (important in India; diagnosed by nerve thickening + sensory/motor deficit, smears often negative).
• Histoid leprosy: a variant of LL with shiny cutaneous nodules, very high BI, classically due to dapsone resistance/irregular treatment; histology shows spindle-shaped histiocytes.

WHO operational classification (treatment-based)

Type	Skin lesions	Nerves involved	Skin smear
Paucibacillary (PB)	1-5 lesions	Only one nerve trunk	Negative (BI 0)
Multibacillary (MB)	>5 lesions	More than one nerve	Positive at any site

High-yield: WHO rule — any single positive slit-skin smear makes the case MB regardless of lesion count. PNL is treated as MB if nerves are multiple. When in doubt, classify and treat as MB.

Mnemonic for the spectrum direction: "Tuberculoid is Tough immunity, Lepromatous is Lousy immunity." As you move TT → LL: bacilli increase, lepromin becomes negative, lesions multiply and symmetrise, sensory loss becomes diffuse, and CMI falls.

Clinical features — what to look for

The cardinal clinical triad (and WHO case-definition cardinal signs):

1. Hypopigmented or reddish skin patch with definite loss of sensation (anaesthesia, anhidrosis, hair loss).
2. Thickened/enlarged peripheral nerve with or without tenderness, plus loss of function (sensory/motor/autonomic).
3. Positive slit-skin smear for acid-fast bacilli.

A WHO diagnosis needs at least one cardinal sign.

Nerves most commonly thickened (examine these on the patient):

• Ulnar nerve — at/above the medial epicondyle (most commonly affected overall) → claw hand (ring + little finger), wasting of hypothenar/interossei.
• Median nerve → ape thumb, loss of thumb opposition.
• Common peroneal (lateral popliteal) — at neck of fibula → foot drop.
• Posterior tibial → claw toes, plantar anaesthesia, plantar ulcers.
• Great auricular — most visibly thickened nerve (seen across the neck).
• Radial cutaneous, facial (zygomatic branch → lagophthalmos), supraorbital, supratrochlear.

High-yield: Sensory loss precedes motor loss. Order of sensory loss in a leprosy patch: temperature (first) → pain → touch (last). Test with cotton wool (touch) and warm/cold tubes.

Lepromatous-specific signs: madarosis (loss of lateral eyebrows), leonine facies, saddle-nose deformity, nasal stuffiness/epistaxis (early sign, mucosa loaded with bacilli), gynaecomastia and testicular atrophy (orchitis), and diffuse infiltration without discrete patches.

Diagnosis & investigations

Diagnosis is largely clinical, confirmed by slit-skin smear and biopsy. The investigations test the bacterial load and the immune status.

1. Slit-skin smear (SSS) — investigation of choice for bacillary load

Technique (stepwise): Pinch the skin to make it bloodless → make a small incision ~5 mm long, 2-3 mm deep → scrape the dermis to collect tissue fluid/pulp → smear, stain with Ziehl-Neelsen (or Fite-Faraco) stain.

Standard sites (minimum): both ear lobes + the most active skin lesions (classically 6 sites: 2 ear lobes + 4 lesions). Ear lobe is highly sensitive because it is cool and superficial.

Two quantitative indices are read:

Index	What it measures	Scale	Notes
Bacteriological Index (BI) of Ridley	Total bacilli (live + dead) per oil-immersion field	0 to 6+ (logarithmic)	1+ = 1-10 bacilli per 100 fields; 6+ = >1000 per field with globi. Used to monitor and classify.
Morphological Index (MI)	% of solid-staining (viable) bacilli of total counted	0-100%	Falls rapidly with effective treatment; indicator of infectivity and drug response. Dead bacilli stain fragmented/granular/beaded.

High-yield: BI reflects total bacterial mass and falls slowly (~1+ per year); MI reflects live bacilli and is the best early marker of treatment response (drops to near 0 within months of effective MDT).

2. Lepromin (Mitsuda) test — measures immunity, NOT a diagnostic test

• Antigen: lepromin (heat-killed M. leprae) injected intradermally; not used to diagnose leprosy but to classify and assess prognosis/CMI.
• Two reactions read:
  • Fernandez reaction — early, at 48-72 hours = delayed hypersensitivity (analogous to Mantoux).
  • Mitsuda reaction — late, at 21 days (3-4 weeks) = granuloma formation; the one classically reported.
• Positive (induration/nodule): TT and BT (good CMI). Negative: LL, BL, and infants (immature CMI). Useful prognostically — a positive test means the disease is contained.

High-yield: Lepromin test is positive in tuberculoid, negative in lepromatous, and is a test of host immunity, not infection — a healthy contact can be positive.

3. Histopathology / nerve biopsy

• Skin biopsy from the active edge; nerve biopsy (e.g., sural or radial cutaneous) is the investigation of choice in pure neuritic leprosy.
• LL: Grenz zone (clear subepidermal band), sheets of foamy macrophages (Virchow/lepra cells) stuffed with bacilli forming globi (cigar-bundles).
• TT: well-formed epithelioid granulomas with Langhans giant cells, lymphocytes, nerve destruction, no demonstrable bacilli.

4. Other tests

• PCR for M. leprae DNA — most sensitive, useful in PB/PNL and smear-negative cases.
• Serology: anti-PGL-1 IgM antibodies (high in MB, low/absent in PB) — research/epidemiological use.
• Histamine test (no triple-flare response over a patch) and pilocarpine sweat test (no sweating) demonstrate autonomic denervation — useful for hypopigmented macules in the field.

Lepra reactions (acute immunological episodes)

Reactions are the main cause of nerve damage and disability and are commonly asked.

Feature	Type 1 (Reversal/RR)	Type 2 (ENL)
Mechanism	Type IV (delayed, cell-mediated) — shift in CMI	Type III (immune-complex) ± Type IV
Seen in	Borderline (BT, BB, BL)	LL, BL (high bacterial load)
Skin	Existing lesions become red, swollen, warm	Crops of tender erythematous nodules (erythema nodosum leprosum)
Nerves	Acute neuritis, pain, sudden palsy	Neuritis less common
Systemic	Usually none	Fever, malaise, iritis, orchitis, arthritis, dactylitis
Histology	Oedema, increased lymphocytes	Neutrophilic infiltrate, vasculitis
Treatment	Corticosteroids (prednisolone); continue MDT	Thalidomide (drug of choice), steroids; clofazimine; avoid thalidomide in women of child-bearing age

High-yield: Type 1 reaction = upgrading/reversal, treated with steroids. Type 2 = ENL, treated with thalidomide. Lucio phenomenon (necrotising vasculitis with bizarre ulcers) is a third, severe reaction seen in diffuse non-nodular LL (M. lepromatosis).

Management — MDT (WHO regimens)

Treatment is multidrug therapy (MDT) to prevent resistance. Rifampicin is the most bactericidal drug (kills ~99.9% bacilli with a single dose); dapsone and clofazimine are bacteriostatic/weakly bactericidal.

WHO regimen (current — uniform 3-drug for both, simplified 2018 update gives all patients rifampicin + dapsone + clofazimine):

	Paucibacillary (PB)	Multibacillary (MB)
Rifampicin	600 mg once monthly (supervised)	600 mg once monthly (supervised)
Dapsone	100 mg daily	100 mg daily
Clofazimine	300 mg monthly + 50 mg daily	300 mg monthly + 50 mg daily
Duration	6 months	12 months

(Classically PB used rifampicin + dapsone only; WHO now adds clofazimine to PB as well.)

Key drug facts (favourite MCQs):

• Rifampicin → orange-red urine/secretions, hepatotoxicity; single monthly supervised dose.
• Dapsone → haemolysis (especially G6PD deficiency), methaemoglobinaemia, agranulocytosis, dapsone hypersensitivity syndrome (DRESS-like).
• Clofazimine → reddish-black skin pigmentation (reversible), ichthyosis, GI/abdominal pain (enteropathy); also anti-inflammatory so useful in ENL.
• Single-dose ROM (Rifampicin + Ofloxacin + Minocycline) was used for single-lesion PB.
• Rifampicin (single dose) is the recommended post-exposure prophylaxis (SDR-PEP) for contacts.

High-yield: Patients become non-infectious within ~72 hours of starting rifampicin. MDT is free worldwide (WHO). Relapse is rare; do not stop MDT during a lepra reaction.

Disability grading (WHO)

Grade	Eyes	Hands/Feet
Grade 0	No eye problem due to leprosy	No anaesthesia, no deformity
Grade 1	Anaesthesia but no visible deformity (e.g., reduced corneal sensation)	Loss of protective sensation (anaesthesia), no visible deformity
Grade 2	Visible deformity — lagophthalmos, iridocyclitis, corneal opacity, visual impairment	Visible deformity/damage — ulcers, claw hand, foot drop, absorption

High-yield: Grade 2 disability (G2D) rate is the key programmatic indicator of late diagnosis. The jump from Grade 1 → Grade 2 is visible deformity / visual loss.

Complications

• Deformities: claw hand, foot drop, wrist drop, lagophthalmos, trophic/plantar ulcers, digit resorption.
• Ocular: lagophthalmos → exposure keratitis, iridocyclitis, corneal anaesthesia, blindness.
• Plantar (trophic) ulcers from anaesthesia + repetitive trauma; Charcot joints.
• Secondary amyloidosis (AA) in long-standing LL with recurrent ENL.
• Nasal collapse / saddle nose, septal perforation.
• Drug-related: dapsone haemolysis, clofazimine pigmentation, steroid effects.

Key differentials

• Hypopigmented patch with sensory loss: vitiligo (no sensory loss, depigmented not hypopigmented), pityriasis alba, pityriasis versicolor, post-inflammatory hypopigmentation, naevus depigmentosus/anaemicus — none are anaesthetic.
• Annular plaques: tinea corporis (active scaly edge, KOH positive), granuloma annulare, sarcoidosis, leishmaniasis.
• Nodular/infiltrative LL: sarcoidosis, lymphoma cutis, neurofibromatosis, post-kala-azar dermal leishmaniasis, lupus.
• Thickened nerves without leprosy: hereditary (Déjerine-Sottas, CMT/HMSN), amyloidosis, neurofibromatosis, refsum disease, chronic inflammatory demyelinating polyneuropathy.

Recently asked / exam angle

• Lepromin test is for classification/prognosis, NOT diagnosis — positive in TT, negative in LL and infants; Mitsuda read at 21 days.
• WHO MB vs PB cut-off = 5 lesions; any positive smear = MB.
• Morphological Index is the best marker of viability and treatment response; BI for total load.
• Type 1 reaction → steroids; Type 2 (ENL) → thalidomide. Match reaction to spectrum (RR = borderline, ENL = LL/BL).
• Ulnar nerve = most commonly involved; great auricular = most visibly thickened; common peroneal → foot drop.
• Earliest sensation lost in a patch = temperature.
• Grenz zone + foamy Virchow cells + globi = LL histology; epithelioid granuloma + Langhans giant cells = TT.
• Clofazimine → skin pigmentation; dapsone → haemolysis (G6PD); rifampicin → orange urine.
• Lucio phenomenon and M. lepromatosis association.
• Patient non-infectious within 72 hours of rifampicin; single-dose rifampicin = PEP for contacts.

Rapid revision

1. M. leprae — acid-fast, cannot be cultured, generation time ~12-14 days, grows at cool sites (skin, nerves, eye, testis).
2. Schwann cell entry via PGL-1 + laminin-2/α-dystroglycan; nine-banded armadillo is the animal model/reservoir.
3. Ridley-Jopling: TT → BT → BB → BL → LL; as you go right, bacilli increase, lepromin negative, CMI falls (Th1 → Th2).
4. WHO: PB = 1-5 lesions/one nerve/smear-negative; MB = >5 lesions/multiple nerves/smear-positive (any positive smear = MB).
5. Cardinal signs: hypopigmented anaesthetic patch + thickened nerve + positive slit-skin smear (any one diagnoses).
6. Sensory loss order in a patch: temperature → pain → touch; sensory loss precedes motor.
7. SSS from ear lobes + lesions; BI = total load (0-6+), MI = % viable (treatment/infectivity marker).
8. Lepromin (Mitsuda) read at 21 days — positive in tuberculoid, negative in lepromatous/infants — tests immunity, not infection.
9. LL histology: Grenz zone, foamy Virchow cells, globi; TT histology: epithelioid + Langhans giant cells, no bacilli.
10. MDT: Rifampicin (monthly, most bactericidal) + Dapsone + Clofazimine — PB 6 months, MB 12 months; non-infectious in ~72 h.
11. Type 1 (reversal, borderline) → steroids; Type 2 (ENL, LL/BL) → thalidomide; Lucio phenomenon in diffuse LL.
12. WHO Grade 2 disability = visible deformity / visual impairment — marker of delayed diagnosis.