NAME OF DISEASE: Leprosy
ETIOLOGICAL AGENT: Mycobacterium leprae,
an acid fast, Gram+, rod-shaped obligate
intracellular organism. Grown in armadillos. It cannot be grown in agar
A chronic intracellular infectious disease unique to man. Usually it is not fatal. The manifestations of the disease depend on the resistance of the host. Types:
1. Tuberculoid - host is
highly resistant, clinical abnormalities limited to a few peripheral nerves
and adjacent skin areas, tuberculoid granuloma
2. Lepromatous - host lacks resistance, all tissues affected, foam cell granuloma
3. Borderline - between tuberculoid and lepromatous
The earliest clinically detectable lesions of leprosy involve the skin and show histologic association with sebaceous glands and hair follicles. From the onset, small cutaneous nerve fibers are involved. With bacillary multiplication, contiguous skin areas, including autonomic nerve fibers, dermal appendages, and blood vessels, are invaded.
Lymphohematogenous dissemination of bacilli is probably an early phenomenon. As infection spreads along sensory nerves, motor fibers within parent nerve trunks are damaged. Leprosy bacilli are unable to penetrate directly into the nervous system proximal to the dorsal root ganglions; central nervous system infection does not occur.
When there is dense proliferation of leprosy bacilli, as in lepromatous leprosy, bacteremia is virtually continuous, and bacilli are easily demonstrable in many organs. Yet, there is little systemic reaction, and tissue destruction occurs mainly in cool, superficial locations: the skin (except in folds); peripheral nerves in subcutaneous loci, oral and nasopharyngeal mucous membranes (not enteric or vaginal); the testes (not the ovaries); and the anterior third of the eye.
The earliest clinically detectable form of leprosy is called indeterminate leprosy because the ultimate host response is not yet apparent. The lepromin skin test may be of prognostic value.
Leprosy is seldom suspected because the only manifestations are a few flat, ill-defined skin lesions on the face or trunk, with minimal sensory changes. It is a history of contact with a patient known to have leprosy that provokes appropriate investigation; only a skin biopsy with the demonstration of acid-fast bacilli (extremely sparse) in nerves can establish the diagnosis.
When cell-mediated immunity is well developed, the pattern is that of tuberculoid leprosy. Clinical manifestations are limited to no more than one or two nerves and the related skin areas. However, biopsies of apparently normal nerves have occasionally demonstrated acid-fast bacilli, suggesting that the disease is disseminated at the outset. The typical tuberculoid lesion is a large (3-30 cm) erythematous plaque with sharp outer margins fading centrally to a flattened clear zone of healing that is rough, anhidrotic, hairless, hypopigmented, and anesthetic.
If effective cell-mediated immunity fails to develop, lepromatous leprosy is the result. The early lesions of lepromatous leprosy are multiple, symmetrically distributed, erythematous ill-defined macules and papules. The macules are shiny and may be perceptible only when viewed in obliquely incident sunlight. Plaques and nodules ultimately develop, although in some Latin American patients only diffuse waxy infiltration of the skin may be seen (diffuse lepromatosis or "spotted leprosy").
In advanced cases, virtually the entire skin surface is infiltrated by bacilli so that even normal-appearing areas may be grossly infected. Enormous numbers of bacilli are present and there is continuous bacteremia with heavy seeding of multiple organs. Yet, fever, anemia, leukocytosis, and other manifestations of overwhelming infection are absent.
Clinical Features of Advanced Lepromatous Leprosy
|Skin||Symmetrically distributed macules, papules, plaques, and nodules (lepromas); loss of eyebrows and eyelashes; rarely, loss of scalp hair; leonine facies (accentuation of features by infiltration and nodules); thickened pendulous ears; spider telangiectasias; edema of extremities (invasion of lymphatics)|
|Eyes||Conjunctival and episcleral nodules; beading of corneal nerves; superficial punctate keratitis, interstitial keratitis with pannus formation of chronic plastic iridocyclitis|
|Upper respiratory||Nasal stuffiness, coryza, epistaxis; ulcers of uvula and tonsils, loss of teeth (oropharyngeal infiltration); septal perforation, nasal collapse (destruction of cartilaginous septum), hoarseness, stridor, asphyxia (laryngeal infiltration)|
|Other organs/systems||Hepatomegaly, splenomegaly lymphadenopathy, testicular invasion and destruction, gynecomastia, cystic bone changes in the distal phalanges, and skeletal muscle invasion. Kidneys are spared unless immune complex nephritis or amyloidosis occurs.|
|Serum||Hypergammaglobulinemia (polyclonal), elevated immunoglobulins (especially IgG), biologic false positive serologic tests for syphilis, antithyroglobulin antibody, rheumatoid factor, positive LE cell preparations, cryoglobulinemia|
Borderline (Dimorphous) Leprosy
Leprosy in most patients falls between the two polar forms (tuberculoid and lepromatous) of the disease. The lack of focalization in patients with borderline leprosy reflects the precarious nature of the balance between bacillary multiplication and cellular immunity.
The skin lesions are smaller, more numerous, less nearly anesthetic, and less sharply marginated in borderline leprosy than in tuberculoid leprosy. Band-like lesions with sharply punched-out centers are common. There is low-grade bacteremia, and granulomas are present in the lymph nodes, liver, testicles, and other organs.
The feature common to all forms of leprosy is nerve infection. Nerve damage appears to result from the multiplication of bacilli within Schwann's cells and damage to the perineurium, which is partially replaced by Schwann's cells. Most of the deformity in leprosy is based upon trauma to, or secondary infection of, denervated tissues. Bacillary multiplication and nerve destruction are most intense at certain superficial sites of predilection.
Sites of Peripheral Nerve Enlargement and Damage in Leprosy in Approximate
Descending Order of Frequency*
|Ulnar||Elbow & several inches above||Clawing of 4th & 5th fingers, wasting of intrinsic hand musculature|
|Posterior tibial||Between medial malleolus & heel||Clawing of toes, plantar anesthesia|
|Superficial peroneal||Winding around neck of fibula||Foot drop|
|Greater auricular||Crossing sternocleidomastoid muscle in neck||Cosmetic importance only|
|Median||Antecubital fossa or just proximal to carpal tunnel in wrist||Thenar wasting, loss of opposability of thumb, palmar anesthesia|
|Radial||Winding around radius at wrist||Wrist drop (unusual)|
|Facial||Crossing zygoma or near stylomastoid foramen||Relatively selective damage to temporal & zygomatic branches, resulting in inability to close eye (lagophthalmos)|
|Trigeminal||Emerging from respective foramina||Anesthesia of face, cornea, & conjunctiva|
|Supraorbital||Above the eyes||Cosmetic importance only|
Anesthesia to heat and cold are lost before other modalities. Late sequelae of nerve damage include vasomotor and trophic changes, infection and ulceration of anesthetic parts, pyogenic osteomyelitis, muscle wasting, and resorption of soft tissue and bone. The involved nerves may be firm, tender, and enlarged both visibly and palpably.
With the exceptions of pure neural and indeterminate leprosy, the diagnosis is not necessarily elusive (provided it is considered), and it is best established by punch biopsies of skin lesions. Biopsies should be deep enough to include fat. The diagnosis of neural leprosy requires biopsy of a cutaneous nerve twig. Stained smears are examined for acid-fast bacilli.
The differential diagnosis of leprosy can include a broad variety of skin diseases ranging from tinea versicolor to pityriasis rosea to erysipelas. Local areas of cutaneous anesthesia and enlarged peripheral nerves are the critical clues.
Erythema Nodosum Leprosum (ENL). ENL is consequent on the formation and deposition of antigen-antibody complexes in various tissues. It is characteristic of lepromatous or near-lepromatous leprosy and generally occurs in patients who are receiving and responding to chemotherapy, although spontaneous ENL also occurs. ENL is not associated with a shift along the clinical leprosy spectrum. There is a wide range of severity, a tendency toward persistence or recurrence, and a tendency to be precipitated by a variety of stresses (i.e., pregnancy, emotion, menstruation).
Histologically, ENL is characterized by vasculitis and panniculitis. Polymorphonuclear leukocytes are predominant early, and microabscesses may form. The characteristic clinical manifestations of ENL are disseminated nodular skin lesions which are red, hot, and tender. They occur in crops of a few to hundreds and usually involve the face, trunk, and extremities. The lesions are rarely restricted to the pretibial areas. Although most of the skin surface is involved with M. leprae in lepromatous leprosy, ENL lesions bear no particular relationship to the local concentration of bacilli. In particularly violent ENL episodes, the skin nodules may undergo frank suppuration with abundant acid-fast bacilli in the purulent exudate. Other manifestations of ENL include erythema multiforme, episcleritis, acute iridocyclitis, lymphadenitis, polyneuritis, orchitis, polyarthritis, bone pain, edema, hypoalbuminemia (from increased vascular permeability), inflammation of the glottis (sometimes requiring glucosteroids and/or tracheostomy), glomerulonephritis, and rarely hemolytic anemia.
Lucio Phenomenon (Erythema Necroticans). This complication is unique to diffuse lepromatosis leprosy and usually occurs in Latin American patients. The development of necrotizing vasculitis results in crops of large polygonal lesions characterized by ulcerations and sloughing of large areas of skin. The pathophysiology of this complication is not fully delineated, but it may represent a variant of ENL.
Amyloidosis. Deposition of amyloid in various tissues.
Although years are required for the elimination of M. leprae from the skin, most bacilli are dead within 3-6 months of the initiation of effect therapy. The shedding of viable M. leprae in nasal secretions and bacteremia also cease within 3-6 months. Therefore, except for the first few months of treatment, outpatient management is adequate for the vast majority of patients. To minimize the possibility of relapse, therapy should be continued until all M. leprae have disappeared from the skin, a matter of at least 5 years in lepromatous patients. However, lifelong chemotherapy is indicated in patients who fail to recover lepromin reactivity because persisting mycobacteria predispose these patients to relapse. Patients with tuberculoid leprosy should be treated for 1-2 years beyond the resolution of apparent lesions. The role of physiotherapy, psychotherapy, and plastic surgery in rehabilitation of the leprosy patient cannot be overemphasized.
Dapsone. The antimicrobic of choice for the treatment of leprosy is dapsone (DDS:4,4'-diaminodiphenylsulfone), a bacteriostatic drug that interferes with folic acid synthesis. Conventional oral doses of 50-100 mg DDS per day produce serum levels which are 100-200 times the MIC. A satisfactory response may also be expected in patients treated with 200-500 mg once weekly, because effective concentrations persist in the serum for 7 days.
Rifampin. The first antimicrobic known to be bactericidal against M. leprae, rifampin acts with greater rapidity than any previously available drug. The recommended dose is 600 mg daily. Because the drug is currently so expensive, its principal role is adjunctive in the treatment of lepromatous leprosy. Despite alleged immunosuppressive properties, rifampin may still precipitate ENL.
Clofazimine. This is a secondary drug of choice that is used in conjunction with dapsone or rifampin in a combined chemotherapy regimen. It is bacteriocidal, non-toxic and effective but expensive. It does cause a temporary skin discoloration. It is given orally at 100 mg/day, three days per week.
Ethionamide/Prothionamide. These drugs are analogues of isonicotinamide and as such they act by blocking mycolic acid biosynthesis. They are interchangeable in a chemotherapy regimen. Either may be used in a combined chemotherapy regimen with either dapsone or rifampin. They are bacteriocidal. They are administered orally at 500-1000 mg/day, three days per week.
Thalidomide (Thalomid). This drug was originally developed as a sedative and morning-sickness pill but was subsequently found to cause severe birth defects; the Food and Drug Administration then banned it. Under the new regulations there are a number of restrictions on its use:
1. It can be used only for the treatment of erythema nodosum leprosum.
2. Doctors who prescribe
the drug and pharmacists who dispense it must register with
Celgene, the company that produces it.
3. Women must have a negative pregnancy test 24 hours before taking the drug.
4. Women must get weekly pregnancy
tests during the first month of treatment. Thereafter they
must get once-a-month pregnancy tests.
5. All thalidomide users
must enroll in a registry at Boston University that will record any
pregnancies that occur and their outcomes.
6. All male patients must
use condoms during sexual intercourse because the drug is found in