eMedicine Specialties > Neurology > Neurological Infections

Leprosy: Treatment & Medication

Author: Ramaratnam Sridharan, MBBS, MD, Head, Department of Neurology, Professor of Neurology, Chennai Neurospeciality and Research Institute, India
Coauthor(s): Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants; Lakshmi Narasimhan Ranganathan, MD, Tutor, Institute Of Mental Health, Chennai, India; Senior Civil Assistant Surgeon, Tamil Nadu Medical Services; Srinivasaraman Govindarajan, DMRD, DNB, Fellow in Radiology, Barnard Institute of Radiology, India
Contributor Information and Disclosures

Updated: Feb 27, 2007

Treatment

Medical Care

• US regimens
  • PB disease: Dapsone 100 mg/d plus rifampin 600 mg/d for 1 year, then stop treatment
  • MB disease: Dapsone 100 mg/d plus rifampin 600 mg/d plus clofazimine 50 mg/d for 2 years, then stop treatment. Some US physicians prescribe dapsone indefinitely as prophylaxis to reduce any risk of relapse. This approach appears logical but difficult to maintain in all patients. The National Hansen's Disease Programs (NHDP) believes that stopping therapy after 2 years should be safe if close follow-up can be maintained for the recommended intervals during which relapse is most likely to occur so that therapy can promptly be restarted if necessary. Furthermore, the use of daily rifampin in the United States may also decrease the risk of reactivation in patients with MB leprosy. In the event of intolerance or toxicity to the usual drugs, the NHDP may be contacted regarding recommendations for alternative regimens
• Practitioners in many countries follow the multidrug therapy (MDT) regimen of the World Health Organization (WHO). A WHO study group first recommended MDT in 1981.
  • For adults with MB leprosy, rifampin (rifampicin) 600 mg once monthly, dapsone 100 mg daily, clofazimine 300 mg once monthly, and 50 mg daily are recommended for 12 months. In the rare patient who has evidence of deterioration after MDT for 12 months, he or she can be treated with an additional 12 months of MDT, as for MB leprosy.
  • For PB leprosy in adults, rifampin 600 mg once monthly and dapsone 100 mg daily is given for 6 months. In adults, PB leprosy in a single skin lesion can be treated with single doses of rifampin 600 mg, ofloxacin 400 mg, and minocycline 100 mg. This recommendation is based on the results of a large multicenter trial.
  • For children, the dosage of dapsone is 2 mg/kg/day. Clofazimine 6 mg/kg is given once a month under supervision, and 1 mg/kg daily is self-administered. Rifampin 10 mg/kg is administered once a month.
• Treatment of reactions
  • Reactions require urgent treatment because they can lead to irreversible deformities. Therefore, early diagnosis and timely initiation of anti-inflammatory measures are crucial. MDT should not be stopped but continued at full doses without interruption.
  • Mild cases of reversal reaction may respond to salicylates, chloroquine, or nonsteroidal anti-inflammatory drugs (NSAIDs).
    • Corticosteroids are used when the patient has severe nerve involvement, nerve abscess, or impending paralysis or extensive and acutely inflamed skin lesions. Prednisolone should be prescribed as follows: 40 mg daily for weeks 1 and 2, 30 mg daily for weeks 3 and 4, 20 mg daily for weeks 5 and 6, 15 mg daily for weeks 7 and 8, 10 mg daily for weeks 9 and 10, and 5 mg daily for weeks 11 and 12.
    • The patient should be examined every week, and the dose of corticosteroids should be reduced every 2 weeks. The maximum dosage of prednisolone is 1 mg per kilogram of body weight.
    • Rest, splints, and physiotherapeutic measures are advised.
    • Thalidomide is not useful for reversal reactions.
  • Mild ENL reactions are treated with salicylates, chloroquine, or NSAIDs. Severe ENL reaction is often recurrent and chronic and may vary in its presentation. The management of severe ENL is best undertaken by physician at a referral center. The physician can adjust the dose and duration of antireaction drugs treatment according to the needs of the individual patient. WHO guidelines for the management of severe ENL reaction are given below.
    • If the patient is still receiving antileprosy treatment, continue the standard course of MDT. If MDT is already completed, it need not be restarted.
    • Give adequate doses of analgesics to control fever and pain.
    • Use a standard course of prednisolone at a dosage not exceeding 1 mg/kg/day for a total of 12 weeks.
    • In patients with severe ENL whose disease is not responding satisfactorily to treatment with corticosteroids or in whom the risk of toxicity with corticosteroids is high, a combination of clofazimine and corticosteroids may be used. Start clofazimine 100 mg 2 times a day and continue for a maximum of 12 weeks, along with a standard course of prednisolone. Then, taper clofazimine to 100 mg twice a day for 12 weeks and then 100 mg once a day for 12-24 weeks.
    • Management with clofazimine (dose given above) alone is indicated in patients with severe ENL when corticosteroids are contraindicated: The total duration of treatment with high-dose clofazimine should not exceed 12 months. About 4-6 weeks is needed for clofazimine to take full effect in controlling ENL.
    • Other drug reported to be useful in treating ENL is pentoxifylline, alone or combined with clofazimine and prednisolone.
    • Because of its well-known teratogenic adverse effects, thalidomide should not be used as first-line treatment for ENL associated with leprosy.
    • In exceptional cases, thalidomide may be used in male patients in countries where the drug is licensed for use. The initial regimen is 100 mg 3-4 times daily, which usually controls the reaction within 48-72 hours. The dosage is then tapered over 2 weeks to a maintenance level, usually 50-100 mg/d. Regular attempts should be made to taper or discontinue the drug, but patients may need to continue taking thalidomide for months to years before ENL reactions no longer recur.
    • Other agents, such as intravenous methylprednisolone, plasma exchange, intravenous immunoglobulin, cyclosporine A, alpha-TNF, pentoxifylline oral zinc, and immunotherapy have been used in difficult cases. However, these agents have not been systematically studied.
• Highlights of WHO MDT
  • MDT has been highly successful in controlling leprosy under various conditions since 1982. Relapse with MDT is 0.1% per year for PB and 0.06% per year for MB on average, with a low frequency of adverse effects. Patients with MB leprosy who are taking MDT have significantly reduced frequency and severity of ENL reactions, an effect that may be attributed to the anti-inflammatory effect of clofazimine. MDT can prevent resistance of M leprae to antileprosy drugs because organisms that are resistant to 1 drug are susceptible to other drugs in MDT. Even in the few patients whose leprosy relapses after MDT, retreatment with the WHO MDT regimen has been effective in all.
  • The WHO considers treatment with dapsone or any other antileprosy drug as monotherapy is considered unethical. For patients with PB leprosy, giving MDT until the infection becomes clinically inactive is not necessary because clinical activity does not necessarily imply direct correlation with bacterial multiplication. Nevertheless, the accuracy of the initial classification of patients designated as having PB leprosy is important. Hence, patients with more than 5 skin lesions are treated as if they had MB leprosy. Most patients with MB with a high bacillary index continue to improve even after 12 months without further treatment.
• Future treatment - Drugs under evaluation
  • Minocycline, ofloxacin, and clarithromycin are promising agents being investigated for use in leprosy. These agents have less bactericidal activity than rifampin but are more effective than dapsone or clofazimine and may help to reduce the duration of treatment. Treatment with rifampicin 600 mg/d daily and ofloxacin 400 mg/d for 1 month is being evaluated in both PB and MB leprosy.
  • Ethionamide, prothionamide, thiambutosine, and amithiozone are also under evaluation. They have significant toxic effects.
  • Fusidic acid, ampicillin combined with clavulanic acid, and brodimoprim also have activity against M leprae in vitro or in mice.
  • Clinical trials of many of these new drugs are underway, but the US Food and Drug Administration (FDA) has not approved these drugs for the treatment of leprosy.
  • Levels of tumor necrosis factor (TNF) are increased in leprosy reactions. Thalidomide, which relieves ENL, inhibits TNF release. Analogues of thalidomide without teratogenic effects would have an important role in future therapeutic regimens.
  • PCR may be useful to diagnose early skin lesions, to detect rifampin-resistant strains, and to monitor viability and response to treatment.
• Immunoprophylaxis and immunotherapy
  • No specific and effective vaccine against leprosy is available.
  • Trials of bacille Calmette-Guérin (BCG) plus killed M leprae vaccine, and International Committee of the Red Cross (ICRC) bacillus vaccine yielded 65-70% protective efficacy in trials in India. Other candidate vaccines have been tested, including those against Mycobacterium welchii, Mycobacterium habana, Mycobacterium vaccae, and others. However, none of the candidates or combinations provide a level of efficacy that can be considered a cost-effective intervention for a public health program.
  • BCG immunoprophylactic trials have revealed 20% protection in Burma and 80% in Uganda; India, Papua, New Guinea, and Malawi report rates between these. Endemicity of leprosy in the area, background saprophytic mycobacterial flora, and the age at vaccination may all be relevant factors. Because vaccination may precipitate the clinical appearance of TT leprosy in apparently healthy contacts, immunoprophylaxis is best initiated at an early age.
  • A recent meta-analysis of 7 experimental studies revealed an overall protective effect of 26% (95% confidence interval [CI], 14-37%). The analysis of 19 observational studies overestimated the protective effect at 61% (95% CI, 51-70%). The age at vaccination did not predict the protective effect of BCG. An additional dose of BCG was more protective in the prevention of leprosy compared with a single dose. An additional dose of BCG may be warranted for contacts of leprosy patients in areas where leprosy continues to be a public health problem.
  • India has approved a leprosy vaccine prepared from a killed, nonpathogenic mycobacterial strain for limited clinical use. The intradermal vaccine is designed to be used as an adjunct to standard MDT, to accelerate healing, and to reduce the duration and cost of treatment. Genetically engineered products are likely to replace this first-generation product. A live, nonpathogenic bacillus that replicates in the host is more likely than a killed one to induce cellular immunity.
  • Other immunotherapeutic agents under investigation are immunomodulatory drugs, transfer factor, gamma interferons and IL-2, acetoacetylated M leprae, and delipidified cell components of M leprae. Combined immunotherapy and chemotherapy did not increase the incidence of reactions, was well tolerated, and was beneficial. Modification of defective cell-mediated immunity may be associated with efficient killing and fast clearance of dead bacilli.

Surgical Care

• Surgery improves sensation in selected patients with sensory impairment, and most often prevents further deterioration. Optimal timing for nerve decompression must be established. A multidisciplinary team comprising a leprologist, a neurologist, physical and occupational therapists, and a surgeon with experience in peripheral nerve surgery is needed.
• Surgical treatment of acute nerve abscess consists of careful incision of the nerve sheath and draining the abscess. Surgical neurolysis or even fascicular dissection has been advocated to relieve intraneural pressure. Sensory loss, though generally irreversible, can often be ameliorated by simple longitudinal epineurotomy.
• Surgical treatments for eliminating anatomic constrictions include medial epicondylectomy, anterior transposition of ulnar nerve, deroofing of the carpal tunnel, and decompression of the posterior tibial nerve at the flexor retinaculum.
  • Nerve decompression is undertaken when signs of entrapment have not cleared after 3-4 weeks of steroid therapy, when the patient's neurologic status deteriorates despite steroid therapy, and when signs of nerve abscess or chronic entrapment are noted.
  • Posterior tibial neurovascular decompression by release of the flexor retinaculum with systemic administration of steroids may be beneficial in early acute and silent neuritis. Distal compression of the plantar branches should be relieved by slitting the calcaneal bands and ensuring free passage of the plantar branches to the sole of the foot. Nerve function, particularly autonomic and sensory modalities, recovers to a considerable extent. Some authors believe that, even in long-standing cases, vascular decompression may help in healing chronic plantar ulcers and prevent their recurrence.
• Peripheral nerve reconstruction using denatured muscle autografts may help to restore protective sensation in hands and feet. Nerve grafts may be helpful for patients with localized nerve lesions.
• Cosmetic Surgery in leprosy may be contemplated after medical control of the disease. The procedures include excision of redundant skin in ear lobes and eyelids, excision of excessive breast tissue in gynecomastia, implantation of islands of scalp hair to replace lost eyebrows, and nasal reconstruction.
• Tenodesis may be done to stabilize joints, and arthrodesis may be performed to correct clawing.
• Tendon transfer procedures may be used to replace paralytic muscles with functioning ones, especially to restore dorsiflexion of foot, abduction-opponens action of thumb, extension of the proximal interphalangeal joint, and flexion at the metacarpophalangeal joint.
• Lagophthalmos may be corrected with tarsorrhaphy and canthoplasty or by tunneling a slip of temporalis muscle attached to tendon through the lid and attaching it to the inner canthus. Re-education involves closing jaws to effect eye closure.
• Hopelessly diseased tissue may require surgical amputation.

Consultations

• The Gillis W. Long Hansen's Disease Center, formerly the National Hansen's Disease Center, in Carville, LA, and its regional centers provide consultation and assistance in patient care.
  • In the United States, patients are eligible for treatment by means of the public health service. Contact the Gillis W. Long Hansen's Disease Center, Bureau of Primary Health Care, HRSA 1770 Physician Park Drive, Baton Rouge, LA 70816. Telephone  800-642-2477  (toll free) or  225-642-4736, fax 225-642-4748.
  • In the United States and in countries where leprosy is uncommon, patients with leprosy are best referred to specialized centers with expertise in leprosy management.
  • In areas of endemic leprosy, individual physicians may adhere to policies of local health authorities. Even in these areas, referral to a specialized center would be indicated in nonresponders, patients who do not tolerate the MDT regime, those with severe reactions, or those in whom other diagnoses have not been excluded.
• Consultation with an ophthalmologist is recommended for management of ocular complications.
• Consultation with an otorhinolaryngologist may be helpful for patients who have nasal symptoms.
• Consultation with an orthopedic surgeon is recommended for management of trophic ulcers and tendon transfer surgery.
• A cosmetic surgeon should be consulted for correction of facial deformities.
• Consultation with a specialist in physical medicine and orthotics may be helpful.
  • Physiotherapy is essential in patients with paralysis due to neural involvement. In patients who undergo rehabilitative surgery, such as tendon transfers, muscle reeducation exercises are essential.
  • The most effective healing tools for plantar ulceration are the total contact cast (TCC) and the posterior walking splint (PWS).
  • If the TCC and PWS are not appropriate, alternative pressure relieving devices or healing devices such as the Carville custom sandal, Plastizote boot, and prefabricated healing sandals or shoes can be made, modified, or augmented to remove the load from the foot. The footbed of the Plastizote boot is molded the same way as a Carville sandal, but the upper part is made of Plastizote and rises to just below the gastrocnemius muscle belly. This device adds support for moderately to severely deformed feet, such as resolved Charcot fractures, during showering, bathing, or household activities.
  • Heel ulcers are common in patients with insensitive feet because of long-term bedrest or positioning during surgery. These ulcers can be on the medial, lateral, or posterior aspect, with some plantar component. The boot is cut out to appropriately relieve the affected area. The boot should be worn at all times, especially when the involved foot is in contact with any surface (eg, bed, recliner, foot stool, sofa).
  • When the wound closes, permanent footwear and orthotics are fitted to prevent reulceration.
  • All options used for the wound-healing phase and initial ambulation after wound closure must include an assistive device for partial weight bearing, preferably crutches or a walker.

Diet

Most patients can have a normal diet. In undernourished patients, a high-protein diet may be beneficial.

Activity

Normal activities are appropriate, except for patients with sensory loss and at risk for trophic ulcers.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Leprostatic agents

These agents have antibiotic properties against M leprae.

Dapsone (Avlosulfon)

Diamino diaphenylsulfone (DDS) is bacteriostatic. Resistant organisms may emerge with monotherapy. Inhibits incorporation of PABA into folic acid. Slowly and nearly completely absorbed from GI tract. Peak plasma concentration in 1-3 h; half-life 10-50 h (mean, 28 h). Distributed throughout body water to all tissues and tends to be retained in skin, liver, kidney, and muscle. Acetylated in liver (genetically determined).

Clofazimine (Lamprene)

Phenazine dye, binds to DNA template and inhibits function. Weakly bactericidal; has anti-inflammatory effects. Absorbed orally, accumulates in tissues. Half-life >70 d. Loading dose of 300 mg once per month (under supervision) given in leprosy-control programs in addition to daily dose; this approach ensures that optimal amount maintained in body tissue, even if patient occasionally misses daily dose.

Antitubercular agents

The drug of choice is rifampin.

Rifampin (Rifadin, Rimactane)

Single 600-mg can kill 99.9% or more of viable M leprae, probably because of slow doubling time of bacilli or delayed effect of drug; rate not dose related. High bactericidal activity makes once-monthly application feasible and cost-effective for leprosy-control programs. Inhibits DNA-dependent RNA polymerase of Mycobacteria and other microorganisms, suppressing start of chain formation in RNA synthesis.
Oral administration produces peak plasma concentrations in 2-4 h; eliminated in bile; deacetylated metabolite has full antibacterial activity. Enzyme induction progressively shortens half-life during first 14 d of therapy.
Dose adjustment not necessary for impaired renal function. M leprae resistant to rifampin reported, mainly in areas where rifampin given alone or with dapsone, to dapsone-resistant patients, or where selective noncompliance to dapsone or clofazimine occurred.

Antibiotics

Therapy should cover all likely pathogens in the context of the clinical setting.

Minocycline (Dynacin, Minocin)

Inhibits protein synthesis by binding to 30S ribosomal subunit at site that blocks binding of amino acid–charged tRNA to acceptor site of the ribosomal mRNA complex. Drug accumulates in cells of susceptible organisms by mean of an energy-dependent mechanism. Passes through enterohepatic circulation and primarily excreted in urine

Ofloxacin (Floxin)

Interferes with DNA synthesis by binding to topoisomerases II and IV to cause bacterial lysis. Elimination through kidneys by active tubular secretion, which probenecid can block.

Clarithromycin (Biaxin)

Binds to 50S ribosomal subunit of bacteria. Inhibits protein synthesis by interfering with tRNA translocation and inhibiting formation of initiation complex. Well absorbed when given orally; excreted after hepatic metabolism and as intact drug in urine; 14-hydroxy metabolite has antimicrobial activity.

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