Lepra Reactions & Complications
Dermatology · Leprosy · lean revision notes
Lepra Reactions & Complications
Lepra reactions are acute, immunologically mediated episodes of inflammation that interrupt the otherwise chronic, indolent course of leprosy. They are the single most important cause of nerve damage and permanent disability in leprosy, and they can occur before, during, or after multidrug therapy (MDT). Recognising the two reaction types and treating them promptly is a high-yield, repeatedly tested theme.
High-yield: Reactions are NOT a sign of treatment failure or relapse. MDT must be CONTINUED throughout the reaction — you treat the reaction in addition to, not instead of, anti-leprosy chemotherapy.
Classification of Lepra Reactions
There are two distinct immunological reactions plus a third rarely-asked entity:
| Reaction | Eponym/Name | Immunological basis | Spectrum affected |
|---|---|---|---|
| Type 1 | Reversal reaction (RR) | Type IV — delayed cell-mediated hypersensitivity (CMI) | Borderline: BT, BB, BL |
| Type 2 | Erythema nodosum leprosum (ENL) | Type III — immune-complex deposition + neutrophils | Lepromatous: BL, LL |
| Lucio phenomenon | Lucio leprosy/erythema necroticans | Thrombotic vasculopathy, endothelial invasion | Diffuse non-nodular LL (Lucio–Latapí), Mexico/C. America |
High-yield: Type 1 reaction occurs in borderline leprosy (BT–BB–BL, the immunologically unstable middle of the Ridley–Jopling spectrum). Type 2 (ENL) occurs in multibacillary lepromatous disease (BL and LL), where antigen load is highest.
A quick anchor: the Ridley–Jopling spectrum runs TT → BT → BB → BL → LL. The borderline forms are immunologically unstable and "swing." A swing TOWARDS the tuberculoid pole (improving CMI) is an upgrading/reversal reaction; a swing TOWARDS the lepromatous pole (waning CMI) is a downgrading reaction. Both are Type 1 events — the difference is the direction of the immunological shift.
Type 1 (Reversal) Reaction
Pathophysiology
A sudden change in cell-mediated immunity to Mycobacterium leprae antigens in the borderline patient. Upgrading reactions (the common type, often triggered by starting MDT as bacilli die and release antigen) reflect a surge of T-cell mediated (Th1) immunity. There is delayed-type hypersensitivity with increased IFN-γ and TNF-α at sites of antigen — chiefly skin lesions and peripheral nerves. The hallmark histology shows oedema and epithelioid granuloma formation.
Clinical features
The cardinal feature is that existing lesions become acutely inflamed — they do not appear as new crops of separate lesions (a useful contrast with ENL).
- Pre-existing skin patches/plaques become erythematous, swollen, warm, tender, and shiny; they may desquamate or ulcerate.
- Acute neuritis — nerves become painful, tender, and enlarged. This is the dangerous component. The ulnar, median, common peroneal (lateral popliteal), facial, and posterior tibial nerves are vulnerable.
- Oedema of hands, feet, and face.
- Systemic upset is usually mild — little or no fever, no malaise typically.
- No erythema nodosum, no iridocyclitis, no systemic vasculitic features.
High-yield: A "silent neuritis" — nerve function loss WITHOUT pain — can occur in Type 1 reactions. This is why regular voluntary muscle testing (VMT) and sensory testing (ST) are mandatory during follow-up; nerve damage may be detected only on examination.
Stepwise approach to suspected Type 1 reaction
Suspected Type 1 reaction → assess for nerve involvement (pain/tenderness/palpable enlargement/sensory or motor loss) → document VMT + ST + nerve tenderness → grade severity (mild vs severe) → start corticosteroids if severe → continue MDT → monitor nerve function and taper.
Type 2 Reaction (Erythema Nodosum Leprosum, ENL)
Pathophysiology
ENL is an immune-complex–mediated (Type III) systemic illness occurring in patients with a heavy bacillary load (BL/LL). Antigen–antibody complexes deposit in skin, nerves, joints, and other organs, activating complement and recruiting neutrophils (the histological hallmark, distinguishing it from the lymphocyte/epithelioid picture of Type 1). TNF-α is a central mediator — which explains the dramatic response to thalidomide, a TNF-α inhibitor.
Clinical features
ENL is a multisystem inflammatory disorder:
- Crops of new, tender, erythematous subcutaneous nodules (erythema nodosum–like) appearing on the extensor surfaces of limbs and the face — these are NEW lesions, not inflammation of old patches.
- Marked systemic features: high fever, malaise, prostration.
- Iridocyclitis (anterior uveitis) — a leading cause of blindness in leprosy.
- Orchitis/epididymo-orchitis → testicular atrophy and infertility.
- Neuritis (less acute/severe than Type 1 usually, but can occur).
- Arthritis, dactylitis, lymphadenopathy, nephritis (glomerulonephritis), hepatosplenomegaly.
- Severe/chronic ENL may produce pustular or necrotic (ulcerated) nodules.
High-yield: ENL nodules are NEW, tender, on extensors, with high fever and systemic signs (iridocyclitis, orchitis, arthritis). Type 1 lesions are OLD lesions turning red and swollen with little systemic upset.
Type 1 vs Type 2: The Comparison Table
| Feature | Type 1 (Reversal) | Type 2 (ENL) |
|---|---|---|
| Spectrum | Borderline (BT, BB, BL) | Lepromatous (BL, LL) |
| Immunology | Type IV — cell-mediated (delayed hypersensitivity) | Type III — immune complex |
| Cytokine | IFN-γ, TNF-α | TNF-α (immune complexes) |
| Histology | Oedema, epithelioid granuloma, lymphocytes | Neutrophilic infiltrate, vasculitis |
| Skin lesions | OLD lesions inflamed (red, swollen, tender) | NEW crops of tender nodules on extensors |
| Systemic illness | Mild/absent | Severe — fever, malaise |
| Nerve involvement | Common, severe, acute (key danger) | Less common, milder |
| Eye | Spared (except facial nerve → lagophthalmos) | Iridocyclitis common |
| Other organs | Not involved | Orchitis, arthritis, nephritis, hepatosplenomegaly |
| Onset relative to MDT | Often early (first 6 months) | Often later / during therapy, may recur |
| First-line drug | Prednisolone (corticosteroids) | Thalidomide (or steroids); clofazimine for chronic |
High-yield mnemonic — "ENL is the noisier reaction": Extensor Nodules + systemic illness (Eye, Nodes, geNitals/orchitis). Type 1 just "lights up old lesions."
Diagnosis & Investigations
Lepra reactions are clinical diagnoses, made against a background of known or suspected leprosy. There is no single confirmatory laboratory test, but supportive workup helps:
- Slit-skin smear (SSS) for the bacteriological index (BI) — high BI predisposes to ENL; in reactions the BI does not need to fall.
- Skin biopsy — when the diagnosis is uncertain: granulomatous oedema in Type 1; neutrophilic infiltrate/vasculitis in ENL.
- Nerve function assessment — VMT and ST, and palpation for nerve tenderness/enlargement — the most important "investigation" because it dictates urgency of steroids.
- Blood counts/ESR/CRP — leukocytosis and raised inflammatory markers in ENL.
- Slit-lamp examination when ocular symptoms suggest iridocyclitis.
High-yield: The investigation that changes management most is nerve function testing (VMT + ST). Loss of nerve function = severe reaction = urgent corticosteroids, irrespective of skin appearance.
Management
General principles
- Continue MDT — never stop anti-leprosy chemotherapy.
- Treat the reaction simultaneously, tailored to severity and type.
- Protect the nerve and eye — these determine long-term disability.
- Identify and remove precipitants where possible (intercurrent infection, pregnancy/puerperium, vaccination, emotional/physical stress, drugs/iodides).
- Rest and splint the affected limb during acute neuritis; analgesia for pain.
Type 1 (Reversal) reaction
- Mild (skin inflammation only, no neuritis, no new nerve loss): analgesics (paracetamol), rest, reassurance; corticosteroids usually not required.
- Severe (neuritis, nerve function loss, lesions overlying nerves, ulceration, or lesions on face): oral prednisolone is the drug of choice.
- Typical regimen: prednisolone 40 mg/day (some start 1 mg/kg, often ~30–40 mg), tapered over ~12 weeks (3 months), reducing by ~5–10 mg every 2 weeks.
- Early steroids reverse recent nerve damage; established damage (>6 months) responds poorly.
High-yield: Drug of choice for Type 1 reaction = prednisolone (corticosteroids). Clofazimine and thalidomide are NOT first-line for Type 1.
Type 2 reaction (ENL)
ENL is more difficult; therapy depends on severity and chronicity:
- Mild ENL: rest, paracetamol/NSAIDs (analgesia), monitoring.
- Severe/acute ENL (high fever, neuritis, iridocyclitis, orchitis, extensive nodules):
- Thalidomide — the drug of choice for severe/recurrent ENL (highly effective TNF-α inhibitor). Usual dose 100–400 mg/day, tapered.
- Corticosteroids (prednisolone) — used when thalidomide is contraindicated (notably women of child-bearing age), or when there is neuritis/iritis/orchitis requiring rapid control. Steroids and thalidomide may be combined.
- Chronic/recurrent ENL:
- Clofazimine — added in high anti-inflammatory dose (e.g., 100 mg three times daily, then tapered over months) as a steroid-sparing agent. Slow onset (4–6 weeks) limits use in acute attacks but valuable for chronic disease.
- Iridocyclitis: add topical steroid + atropine (mydriatic/cycloplegic); ophthalmology referral.
High-yield (CONTRAINDICATION): Thalidomide is absolutely contraindicated in pregnancy — it is a potent teratogen (phocomelia). In women of child-bearing potential, use corticosteroids/clofazimine instead, with strict contraception if thalidomide is unavoidable.
| Reaction / scenario | Preferred drug |
|---|---|
| Type 1, severe (neuritis) | Prednisolone, taper over ~3 months |
| Type 2 (ENL), severe/recurrent | Thalidomide (DOC) |
| Type 2 in women of child-bearing age | Corticosteroids (thalidomide contraindicated) |
| Type 2, chronic/steroid-sparing | Clofazimine (high dose) |
| Acute neuritis (either type) | Steroids + rest + splinting + nerve protection |
Drug pearls
- Clofazimine — also part of routine MDT; causes reddish-black skin discolouration and ichthyosis. Anti-inflammatory effect is dose-related and slow.
- Thalidomide — TNF-α inhibitor; adverse effects: teratogenicity, peripheral neuropathy, sedation, constipation.
- Corticosteroids — watch for the usual long-course effects (infection risk including reactivation of TB/strongyloides, hyperglycaemia, osteoporosis, peptic ulcer).
Complications of Leprosy & Reactions
The disability burden of leprosy comes overwhelmingly from nerve damage, much of it precipitated by untreated or under-treated reactions.
Nerve damage and deformities
- Ulnar nerve (commonest affected) → claw hand (ulnar claw — clawing of 4th & 5th fingers), loss of intrinsics, sensory loss medial 1½ fingers.
- Median nerve → ape thumb / thenar wasting; combined with ulnar = total/complete claw hand.
- Radial nerve → wrist drop (less common).
- Common peroneal (lateral popliteal) nerve → foot drop.
- Posterior tibial nerve → claw toes, plantar anaesthesia → plantar (trophic) ulcers.
- Facial nerve / zygomatic branch → lagophthalmos (inability to close the eye) → exposure keratitis.
High-yield: Commonest nerve trunk involved in leprosy = ulnar nerve (at the elbow). The great auricular nerve is the most commonly visibly thickened nerve.
Eye complications
- Lagophthalmos (facial nerve), corneal anaesthesia (trigeminal/zygomatic), exposure keratitis.
- Iridocyclitis (ENL) → secondary glaucoma, blindness.
Trophic / secondary changes
- Trophic ulcers of feet (plantar/perforating ulcers) from anaesthesia + repeated trauma.
- Resorption/shortening of digits, contractures, secondary infection, osteomyelitis.
- "Claw hand," "main en griffe," "facies leonina" (LL), saddle-nose, madarosis (loss of eyebrows).
Systemic / amyloidosis
- Chronic ENL and long-standing LL can lead to secondary (AA) amyloidosis → nephrotic syndrome/renal failure.
Lucio phenomenon
- Seen in diffuse, non-nodular lepromatous leprosy (Lucio–Latapí, Mexican). Bacterial invasion of vessel endothelium → thrombosis → angular, painful, necrotic ulcers with crusting, healing with stellate scars. Managed with steroids and full MDT (often poor response; high mortality if septic).
Key Differentials
- Type 1 vs Type 2 reaction — the central exam discrimination (see comparison table).
- Relapse vs reaction — relapse develops slowly with new lesions and a rising BI on smear; reaction is acute and inflammatory. Both are treated WITH continued/restarted chemotherapy — do not mistake a reaction for treatment failure.
- ENL nodules vs idiopathic erythema nodosum — ENL is tender on extensors, recurrent, with systemic leprosy features; classic EN favours shins (anterior) and is associated with streptococcal infection, sarcoidosis, drugs, TB, IBD.
- Cellulitis — Type 1 reaction skin can mimic cellulitis but follows the distribution of pre-existing leprosy lesions and lacks a clear portal of entry.
- Drug-induced reactions / dapsone hypersensitivity (DDS syndrome) — fever, rash, hepatitis, eosinophilia 4–6 weeks after starting dapsone — must be distinguished from a lepra reaction; stop dapsone in DDS syndrome.
Recently asked / exam angle
- "Which reaction occurs in lepromatous leprosy?" → Type 2 (ENL). "Which in borderline?" → Type 1 (reversal).
- "Drug of choice for ENL?" → Thalidomide (severe/recurrent); steroids if pregnancy/iritis/neuritis; clofazimine for chronic/steroid-sparing.
- "Drug of choice for Type 1/reversal reaction?" → Prednisolone.
- "Thalidomide is contraindicated in?" → Pregnancy (teratogen → phocomelia).
- "Immunological basis of ENL?" → Type III immune-complex (neutrophilic, TNF-α). Type 1 = Type IV cell-mediated.
- "Most important step in a patient with a reaction and nerve pain?" → Start corticosteroids and continue MDT (protect the nerve).
- Image/clinical-vignette questions: tender nodules on extensors + fever + uveitis → ENL; old plaque turning red/swollen + tender ulnar nerve → Type 1.
- "Should MDT be stopped during a reaction?" → No — continue MDT.
- Histology slide: neutrophilic infiltrate → ENL; granulomatous oedema/epithelioid cells → reversal.
- Cause of blindness in leprosy → iridocyclitis (ENL) and lagophthalmos (facial nerve, exposure keratitis).
Rapid revision
- Two reactions: Type 1 = reversal (borderline, Type IV CMI); Type 2 = ENL (lepromatous, Type III immune complex).
- Continue MDT through any reaction — reactions are not relapse or failure.
- Type 1: OLD lesions inflame + acute neuritis + mild systemic upset; DOC = prednisolone, taper ~3 months.
- Type 2 (ENL): NEW tender nodules on extensors + fever, iridocyclitis, orchitis, arthritis; DOC = thalidomide.
- Thalidomide contraindicated in pregnancy (phocomelia) → use steroids in women of child-bearing age.
- Clofazimine (high dose) = steroid-sparing agent for chronic/recurrent ENL; slow onset; causes skin discolouration.
- TNF-α is central to ENL → explains thalidomide's efficacy.
- Silent neuritis (painless nerve loss) → do regular VMT + ST; nerve function testing guides steroid use.
- Commonest nerve involved = ulnar; foot drop = common peroneal; lagophthalmos = facial nerve.
- Lucio phenomenon = necrotic angular ulcers in diffuse non-nodular LL (Mexican).
- Histology: ENL = neutrophils/vasculitis; reversal = epithelioid granuloma + oedema.
- Chronic ENL/LL → secondary (AA) amyloidosis; ENL iridocyclitis is a key cause of blindness.