What are the key considerations in the differential diagnosis (ddx) of leprosy in a patient from a region where leprosy is prevalent, such as South Asia, Africa, or Latin America, presenting with skin lesions, numbness, and weakness in the extremities?

Differential Diagnosis of Leprosy

Primary Differential Diagnoses

The differential diagnosis of leprosy must include other granulomatous diseases, particularly tuberculosis, sarcoidosis, cutaneous leishmaniasis, syphilis, and systemic mycoses, as well as non-granulomatous conditions like vitiligo, tinea versicolor, and peripheral neuropathies of other etiologies. 1, 2

Granulomatous Diseases

• Tuberculosis (cutaneous) presents with papulonecrotic lesions, lupus vulgaris, or scrofuloderma, but typically lacks the characteristic peripheral nerve thickening and anesthetic skin lesions seen in leprosy 1, 2

• Sarcoidosis manifests with nodular skin lesions and can involve peripheral nerves, but demonstrates negative acid-fast bacilli on skin smears, elevated serum angiotensin-converting enzyme (sensitivity 60%, specificity 70%), and shows non-caseating granulomas on biopsy without nerve predilection 1

• Cutaneous leishmaniasis produces ulcerative or nodular lesions that may mimic lepromatous nodules, but lesions are typically painful (unlike leprosy), lack sensory loss, and demonstrate Leishmania organisms on tissue smear or biopsy rather than acid-fast bacilli 1, 2

• Tertiary syphilis can present with gummatous lesions and peripheral neuropathy, but serologic testing (RPR/VDRL and treponemal-specific tests) distinguishes it from leprosy 3

Dermatologic Conditions

• Vitiligo presents with hypopigmented macules similar to tuberculoid leprosy, but lesions retain normal sensation, show no nerve thickening, and demonstrate complete depigmentation rather than hypopigmentation 2, 4

• Tinea versicolor produces hypopigmented or hyperpigmented scaly patches that may be confused with indeterminate leprosy, but KOH preparation reveals fungal elements and lesions have normal sensation 2

• Psoriasis can present with erythematous plaques that may resemble borderline leprosy lesions, but demonstrates characteristic silvery scale, lacks sensory loss, and shows different histopathology 4

Neurologic Conditions

• Hereditary sensory and motor neuropathies (Charcot-Marie-Tooth disease) cause peripheral neuropathy with muscle atrophy but lack skin lesions and demonstrate family history with genetic testing confirmation 5

• Diabetic neuropathy produces sensory loss in a stocking-glove distribution but lacks the asymmetric nerve thickening and skin lesions characteristic of leprosy 5

• Guillain-Barré syndrome presents with acute ascending paralysis rather than the chronic, slowly progressive nerve damage of leprosy 5

Other Systemic Diseases

• Systemic lupus erythematosus may present with photosensitive skin lesions and peripheral neuropathy, but demonstrates positive ANA, anti-dsDNA antibodies, and lacks acid-fast bacilli on biopsy 3

• Lymphomas (cutaneous T-cell lymphoma) can produce nodular or infiltrative skin lesions mimicking lepromatous leprosy, but histopathology reveals atypical lymphocytes rather than granulomas with acid-fast bacilli 1, 3

Critical Diagnostic Approach

Confirm leprosy diagnosis by demonstrating at least one WHO cardinal sign: hypopigmented or erythematous skin lesions with definite sensory loss, thickened peripheral nerves on palpation, or positive acid-fast bacilli on slit-skin smear or full-thickness skin biopsy. 2, 4

Essential Clinical Examination

• Systematically palpate all accessible peripheral nerves (ulnar, median, radial cutaneous, common peroneal, posterior tibial, great auricular, and superficial radial nerves) for thickening, tenderness, or nodularity—this finding is pathognomonic when combined with characteristic skin lesions 2, 5

• Test sensation meticulously using light touch, pinprick, and temperature discrimination on all skin lesions, as sensory loss within a skin lesion strongly suggests leprosy over other dermatologic conditions 2, 4

• Examine nasal mucosa for septal perforation, nasal collapse, or mucosal nodules, which occur in advanced lepromatous disease 6, 3

• Assess for lagophthalmos, corneal anesthesia, and facial nerve involvement, as these indicate nerve damage requiring urgent intervention 5, 4

Definitive Diagnostic Investigations

• Full-thickness skin biopsy from the active edge of a lesion remains the gold standard, demonstrating acid-fast bacilli in lepromatous forms or granulomas with nerve involvement in tuberculoid forms 2, 6, 4

• Slit-skin smear from at least six sites (both earlobes, two skin lesions, and both elbows) to calculate the bacterial index, which guides classification as paucibacillary versus multibacillary 2, 4

• Nerve biopsy is indicated when pure neural leprosy is suspected (peripheral neuropathy without skin lesions), as some patients have multibacillary disease in nerves despite paucibacillary skin findings 5

Common Diagnostic Pitfalls

• Delayed diagnosis occurs when physicians fail to consider leprosy in patients from endemic regions (South Asia, Africa, Latin America, Pacific Islands) presenting with chronic skin lesions or unexplained peripheral neuropathy, leading to irreversible nerve damage and disability 7

• Misdiagnosing tuberculoid leprosy as vitiligo or tinea versicolor because sensory testing is not performed on hypopigmented lesions—always test sensation and palpate nerves in any patient with hypopigmented patches from endemic areas 2, 4

• Overlooking "silent neuropathy" where nerve function deteriorates without obvious symptoms or skin reactions, requiring regular nerve function assessment even in clinically stable patients 5

• Failing to recognize leprosy reactions (Type 1 reversal reactions or Type 2 erythema nodosum leprosum) as immunologic phenomena rather than treatment failure or alternative diagnoses, leading to inappropriate treatment discontinuation 2, 5