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Summary Table

Category	Detail
Risk Factors	Prolonged close contact with an untreated case, household contacts, immunocompromised individuals, endemic regions (South/Southeast Asia, Africa, Brazil), poverty, overcrowding
Etiology	Mycobacterium leprae, an obligate intracellular acid-fast bacillus with tropism for Schwann cells; cannot be cultured on artificial media
Patient Presentation	Skin patches (hypopigmented or erythematous) with numbness or loss of sensation; chronic peripheral neuropathy; nasal stuffiness in advanced cases
Classic Physical Exam	Anesthetic hypopigmented skin patches, thickened palpable peripheral nerves (great auricular, ulnar, common peroneal), anhidrosis and alopecia over lesions, claw hand, foot drop, lagophthalmos, madarosis, leonine facies (in lepromatous form)
Key Diagnostic Results	Slit-skin smear showing acid-fast bacilli (positive in multibacillary), skin biopsy with Fite-Faraco stain, clinical diagnosis based on WHO cardinal signs
Management	WHO Multidrug Therapy (MDT): Paucibacillary = Dapsone + Rifampicin for 6 months; Multibacillary = Dapsone + Rifampicin + Clofazimine for 12 months. Lepra reactions managed with corticosteroids or thalidomide
Keywords	"Hypopigmented patch with loss of sensation," "thickened peripheral nerve," "acid-fast bacilli in Schwann cells," "glove-and-stocking neuropathy," "leonine facies," "claw hand," "reversal reaction," "erythema nodosum leprosum"

1. Pathophysiology

Mycobacterium leprae is an obligate intracellular acid-fast bacillus that uniquely targets Schwann cells of peripheral nerves and macrophages in cool body regions. It has the longest doubling time of any known human pathogen, approximately 12 to 14 days, which explains the extremely long incubation period of 2 to 5 years (sometimes up to 20 years). The bacterium cannot be grown on artificial culture media, a fact frequently tested and often used as a distractor against other mycobacterial infections.

The clinical spectrum of leprosy is determined entirely by the host's cell-mediated immune (CMI) response, not by the virulence of the organism itself. This is the single most important concept for understanding leprosy on an exam.

At one pole, patients with a strong CMI response develop tuberculoid leprosy (TT). Their immune system effectively contains the bacilli, resulting in few, well-defined skin lesions with granuloma formation. However, this vigorous immune response also causes significant nerve damage early, because the immune attack on infected Schwann cells destroys the nerve. This is why tuberculoid patients have few bacilli but prominent neuropathy.

At the opposite pole, patients with a weak or absent CMI response develop lepromatous leprosy (LL). The immune system fails to contain the organism, allowing uncontrolled bacterial proliferation throughout the skin, nerves, nasal mucosa, eyes, and testes. This produces numerous, poorly defined, symmetric lesions with a very high bacterial load. Despite the enormous number of organisms, nerve damage in LL tends to be more gradual and diffuse ("glove-and-stocking" pattern) because the destructive granulomatous response is absent.

The bacterium's preference for cool body regions (skin, earlobes, nose, fingers, toes, anterior eye, testes) explains several classic findings: saddle nose deformity (nasal cartilage destruction), madarosis (loss of lateral eyebrows), testicular atrophy and gynecomastia, and the characteristic distribution of skin lesions on cooler extremities while sparing warmer areas like the axillae and groin.

Peripheral nerve involvement follows a predictable pattern. The nerves most commonly affected are those that run superficially through cool areas: the great auricular nerve (visible and palpable in the neck), the ulnar nerve (at the elbow), the median nerve (at the wrist), the common peroneal nerve (at the fibular head), and the posterior tibial nerve (behind the medial malleolus). Damage to these nerves produces the classic deformities: claw hand (ulnar nerve), wrist drop (radial nerve), foot drop (common peroneal nerve), and lagophthalmos (facial nerve).

2. Classification and Clinical Manifestation

WHO Operational Classification

Feature	Paucibacillary (PB)	Multibacillary (MB)
Skin lesions	1 to 5	More than 5
Nerve involvement	Only 1 nerve trunk	More than 1 nerve trunk
Slit-skin smear	Negative	Positive
Ridley-Jopling types	TT, BT	BB, BL, LL
Immune response (CMI)	Strong	Weak

Ridley-Jopling Spectrum

Feature	Tuberculoid (TT)	Borderline Tuberculoid (BT)	Mid-Borderline (BB)	Borderline Lepromatous (BL)	Lepromatous (LL)
Number of lesions	1 to 3	Few (up to 10)	Several	Many	Innumerable, symmetric
Lesion borders	Well-defined, raised	Well-defined	Moderately defined	Poorly defined	Ill-defined, diffuse
Surface	Dry, scaly, hairless	Dry, may have satellite lesions	Variable	Shiny, smooth	Smooth, shiny, diffuse infiltration
Sensation over lesion	Markedly reduced/absent	Reduced	Moderately reduced	Slightly reduced	Minimally reduced (late: glove-and-stocking)
Nerve involvement	Single nerve, early and severe	Few nerves, asymmetric	Several nerves	Many nerves	Diffuse, bilateral, symmetric, late
Bacterial load (BI)	0	0 to 1+	2+ to 3+	3+ to 4+	5+ to 6+
Lepromin test	Strongly positive	Weakly positive	Negative	Negative	Negative
Histology	Epithelioid granulomas with Langhans giant cells, few/no bacilli	Similar to TT but less organized	Mixed	Macrophage granulomas with many bacilli	Foamy macrophages (Virchow/lepra cells), globi, no granulomas

Lepra Reactions (Immunologic Complications)

Feature	Type 1 Reaction (Reversal Reaction)	Type 2 Reaction (Erythema Nodosum Leprosum / ENL)
Mechanism	Delayed-type hypersensitivity (Type IV), CMI upregulation	Immune complex deposition (Type III)
Ridley-Jopling types	Borderline spectrum (BT, BB, BL)	MB forms (BL, LL)
Timing	Often during or after starting treatment	During treatment or even before
Skin findings	Existing lesions become swollen, red, edematous	NEW tender erythematous nodules on normal skin
Nerve involvement	Acute painful neuritis, rapid loss of function	Neuritis, but systemic symptoms predominate
Systemic features	Minimal	Fever, malaise, arthralgia, iridocyclitis, orchitis, lymphadenopathy
Treatment	Corticosteroids (prednisone)	Thalidomide (drug of choice if not pregnant) or corticosteroids; clofazimine for recurrent ENL
Key exam distinction	Worsening of OLD lesions	Appearance of NEW nodules

3. Diagnostic Workup

Test	Role	Key Findings
Clinical examination (WHO cardinal signs)	Best initial diagnostic approach	(1) Hypopigmented/erythematous patch with sensory loss, (2) thickened peripheral nerve, (3) positive slit-skin smear. Any 1 of 3 = diagnosis
Slit-skin smear	Bacteriological confirmation; classifying PB vs MB	Acid-fast bacilli on modified Ziehl-Neelsen; report as Bacterial Index (BI, 0 to 6+) and Morphological Index (MI)
Skin biopsy (Fite-Faraco stain)	Most accurate/confirmatory test	Granulomas with epithelioid cells (TT) or foamy macrophages/Virchow cells with globi (LL); demonstrates nerve involvement
Lepromin test (Mitsuda reaction)	Prognostic (NOT diagnostic)	Positive in TT (strong immunity), negative in LL (weak immunity). Read at 3 to 4 weeks (late/Mitsuda reaction)
Nerve conduction study	Assess nerve damage severity	Reduced conduction velocity, especially in ulnar, median, and common peroneal nerves
*PCR for M. leprae* DNA**	Confirmatory in difficult cases	High sensitivity and specificity, useful in PB with negative smear

The diagnosis of leprosy is fundamentally clinical. The WHO has established three cardinal signs, and the presence of any one of them is sufficient to establish the diagnosis in an endemic setting. These signs are: (1) a hypopigmented or reddish skin patch with definite loss of sensation, (2) a thickened peripheral nerve, and (3) acid-fast bacilli on slit-skin smear.

The slit-skin smear is performed by making a small incision in the skin (typically from the earlobes, elbows, knees, and active lesion margins), scraping dermal tissue, and staining with modified Ziehl-Neelsen stain. The result is reported as a Bacterial Index (BI), graded from 0 (no bacilli in 100 oil-immersion fields) to 6+ (more than 1000 bacilli per field). A positive smear automatically classifies the patient as multibacillary. However, a negative smear does not exclude leprosy, as paucibacillary patients often have a BI of zero.

The most accurate test is a full-thickness skin biopsy stained with Fite-Faraco stain (a modified acid-fast stain that is gentler than standard Ziehl-Neelsen, preserving the waxy M. leprae cell wall). Histopathology reveals the characteristic granulomatous pattern and, critically, demonstrates nerve involvement within the dermis, which is virtually pathognomonic for leprosy.

A frequently tested point: the lepromin test (Mitsuda reaction) is not a diagnostic test. It does not indicate current or past infection. It measures the patient's CMI response to M. leprae antigens and is used for classification and prognosis. A positive result (induration at 3 to 4 weeks) indicates intact CMI, seen in tuberculoid forms. A negative result indicates anergy, seen in lepromatous forms.

Another critical exam point: M. leprae cannot be cultured in vitro on any artificial media. The only laboratory growth models are the mouse footpad (Shepard's method) and the nine-banded armadillo, both used for research purposes. If a vignette describes successful culture of an acid-fast organism from a skin lesion, the answer is NOT leprosy.

4. Management and Treatment

WHO Multidrug Therapy (MDT) Regimen

Component	Paucibacillary (PB)	Multibacillary (MB)
Dapsone	100 mg daily (self-administered)	100 mg daily (self-administered)
Rifampicin	600 mg once monthly (supervised)	600 mg once monthly (supervised)
Clofazimine	Not included	50 mg daily (self-administered) + 300 mg once monthly (supervised)
Duration	6 months (completed within 9 months)	12 months (completed within 18 months)
Single-lesion PB	Alternative: single-dose ROM (Rifampicin 600 mg + Ofloxacin 400 mg + Minocycline 100 mg)	Not applicable

Management of Lepra Reactions

Reaction	First-Line Treatment	Alternative	Key Notes
Type 1 (Reversal)	Prednisolone 40 to 60 mg/day, tapered over 12 weeks	Longer steroid course if neuritis persists	Do NOT stop MDT; continue throughout
Type 2 (ENL), mild	Aspirin or NSAIDs, rest	Clofazimine 300 mg/day tapered	Mild cases without neuritis
Type 2 (ENL), severe	Thalidomide 100 to 400 mg/day (drug of choice)	Prednisolone 40 to 60 mg/day if thalidomide unavailable or contraindicated	Thalidomide is absolutely contraindicated in pregnancy (teratogenic: phocomelia)
Neuritis (acute)	Prednisolone + nerve splinting	Surgical decompression if unresponsive	Treat urgently to prevent irreversible nerve damage

MDT is the cornerstone of leprosy treatment and must always include multiple drugs to prevent resistance. The rationale mirrors tuberculosis therapy: rifampicin is the most potent bactericidal agent, dapsone provides sustained bacteriostatic coverage, and clofazimine adds both bacteriostatic and anti-inflammatory properties (particularly useful in MB disease where ENL reactions may occur).

Rifampicin is given only once monthly under supervision because of its potent bactericidal activity (kills 99.9% of viable M. leprae in a single dose) and to ensure compliance. It is the single most important drug in the regimen.

Dapsone (diaminodiphenyl sulfone) is a folate synthesis inhibitor given daily. Key side effects to know for exams include hemolytic anemia (especially in G6PD-deficient patients, which must be screened before starting), methemoglobinemia, dapsone hypersensitivity syndrome (fever, rash, hepatitis within 6 weeks of starting), and rarely agranulocytosis.

Clofazimine is a riminophenazine dye with both antimycobacterial and anti-inflammatory properties. Its most notable side effect is reddish-brown to violet skin discoloration and ichthyosis (dry, scaly skin), which are reversible after stopping the drug. This cosmetic side effect is a common source of non-compliance and a frequent exam question.

A critical rule: MDT must never be stopped during lepra reactions. Reactions are immunologic events, not treatment failures. Treatment of reactions (corticosteroids or thalidomide) is given alongside continued MDT.

For thalidomide in ENL: it is the most effective agent available, but its use carries an absolute contraindication in women of childbearing potential unless strict pregnancy prevention programs are in place. If thalidomide is contraindicated, corticosteroids are the alternative. Clofazimine at higher doses (300 mg/day) can be used as a steroid-sparing agent for recurrent ENL.

5. Differential Diagnosis and Distractors

Differential	Why It Is Similar	Key Discriminator
Tinea corporis (dermatophytosis)	Annular, hypopigmented, or erythematous patches with raised borders	Tinea has scaling active border with central clearing, no sensory loss, KOH prep shows hyphae. Leprosy patches are anesthetic and anhidrotic
Vitiligo	Depigmented/hypopigmented skin patches	Vitiligo causes complete depigmentation (chalk-white), sensation is fully intact, no nerve thickening. Leprosy patches are hypopigmented (not depigmented) and anesthetic
Pityriasis versicolor	Multiple hypopigmented macules, common in tropical settings	Pityriasis versicolor shows fine scaling, KOH reveals "spaghetti and meatballs" (hyphae + yeast), sensation is intact, lesions are on trunk (sebaceous areas)
Pityriasis alba	Hypopigmented patches, common in children in tropics	Lesions are on the face predominantly, mildly scaly, sensation is intact, self-limiting
Cutaneous tuberculosis (lupus vulgaris)	Granulomatous skin lesion, acid-fast bacilli	Lupus vulgaris shows "apple-jelly nodules" on diascopy, typically on head/neck, does not cause peripheral nerve thickening or sensory loss over lesions
Sarcoidosis	Non-caseating granulomas, skin nodules, neuropathy possible	Sarcoidosis is a systemic disease with bilateral hilar lymphadenopathy, elevated ACE levels, non-caseating granulomas. No acid-fast bacilli, no anesthetic patches
Neurofibromatosis type 1	Palpable peripheral nerve enlargement, skin lesions	NF1 has cafe-au-lait spots (hyperpigmented, not hypopigmented), neurofibromas are soft and non-tender, Lisch nodules on slit-lamp, no sensory loss over skin patches
Systemic lupus erythematosus	Facial rash, potential for multisystem involvement	SLE malar rash is erythematous and spares the nasolabial folds, ANA positive, no peripheral nerve thickening, no anesthetic patches
Secondary syphilis	Widespread skin lesions, symmetric, can mimic lepromatous presentation	Secondary syphilis has condylomata lata, mucous patches, positive RPR/VDRL and FTA-ABS, no nerve thickening, no anesthetic lesions

6. Traps and High-Yield Pearls

The most common way students lose points on leprosy questions is by confusing the two poles of the disease spectrum. The intuitive assumption is that the more severe-looking form (lepromatous, with widespread lesions and high bacterial load) must have the strongest immune response. In reality, it is the opposite: lepromatous leprosy reflects immune failure, while tuberculoid leprosy reflects a robust immune response that limits bacterial growth but paradoxically causes more nerve damage per lesion.

A second frequent trap involves lepra reactions. Students often misinterpret a reaction as treatment failure or drug resistance and select "change antibiotics" or "stop MDT" as the answer. The correct response is always to continue MDT and treat the reaction separately. Furthermore, the distinction between Type 1 and Type 2 reactions hinges on a clean differentiator: Type 1 reactions cause worsening of existing old lesions, while Type 2 (ENL) produces new nodules on previously normal skin. If the vignette describes "new tender subcutaneous nodules with fever" in an MB patient on treatment, that is ENL, and the answer is thalidomide (or corticosteroids if the patient is a woman of childbearing age).

A third trap is the lepromin test. Students who see "skin test" in the context of mycobacterial disease reflexively equate it with a diagnostic tool (like the tuberculin skin test for TB). The lepromin test is not diagnostic. It does not tell you whether the patient has leprosy; it tells you what type of immune response the patient mounts. It is a prognostic and classification tool only.

Finally, any vignette that mentions successful culture of the organism on laboratory media is steering you away from leprosy. M. leprae is one of the very few human pathogens that absolutely cannot be grown in vitro. If culture is positive, consider atypical mycobacteria (M. marinum, M. ulcerans) or other diagnoses entirely.

The core competency being tested in leprosy questions is pattern recognition of the anesthetic hypopigmented patch with peripheral nerve thickening as the unifying finding, combined with understanding the immunologic spectrum that determines disease classification, prognosis, and treatment regimen selection.

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