History
In general, leprosy affects the skin, peripheral nerves, and eyes. Systemic symptoms of leprosy are also possible. Specific symptoms vary with the severity of the disease.
Prodromal symptoms are generally so slight that leprosy is not recognized until a cutaneous eruption is present. However, 90% of patients have a history of numbness first, sometimes years before the skin lesions appear.
Temperature is the first sensation that is lost. Patients cannot sense extremes of hot or cold. The next sensation lost is light touch, then pain, and, finally, deep pressure. These losses are especially apparent in the hands and feet; therefore, the chief complaint may be a burn or ulcer in an anesthetic extremity.
Other parts of the body that might be affected by leprosy are the cool areas, which can include superficial peripheral nerves, the anterior chamber of the eyes, the testes, the chin, malar eminences, earlobes, and knees. From this stage of leprosy, most lesions evolve into the tuberculoid, borderline, or lepromatous types.
Physical Examination
Clinical tests
Certain tests can be performed in the clinic to aid in the diagnosis of leprosy.
Tissue smear testing/slit-skin smears
An incision is made in the skin, and the scalpel blade is used to obtain fluid from a lesion. The fluid is placed on a glass slide and stained by using the Ziehl-Neelsen acid-fast method or the Fite method to look for organisms. The bacterial index (BI) is then determined as the number of organisms at 100X with oil immersion. Skin smears have high specificity but low sensitivity because 70% of all patients with leprosy have negative smear results. However, this test is useful because it detects the most infectious patients.
Histamine testing
This test is used to diagnose postganglionic nerve injury. Histamine diphosphate is dropped on healthy skin and affected skin, and a pinprick is made through each site. The site forms a wheal on healthy skin, but not on skin where nerve damage is present.
Methacholine sweat testing
An intradermal injection of methacholine demonstrates the absence of sweating in leprous lesions. This test is useful in dark-skinned patients in whom the flare with the histamine test cannot be seen.
Diagnostic criteria for leprosy
The diagnosis of leprosy is primarily a clinical one. In one Ethiopian study, the following criteria had a sensitivity of 97% with a positive predictive value of 98% in diagnosing leprosy. Diagnosis was based on 1 or more of the 3 following signs:
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Hypopigmented or reddish patches with definite loss of sensation
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Thickened peripheral nerves with some degree of sensory loss or muscle weakness corresponding to the affected nerve
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Acid-fast bacilli on skin smears or biopsy material
Classification
Leprosy disease classification is used to differentiate types of cutaneous leprosy and helps in determining the prognosis; it has evolved from the 1940s to the present. The most familiar classification systems are the Ridley-Jopling classification (1960s) and a more simplified WHO dichotomy of paucibacillary and multibacillary disease introduced in 1982. The latter system is based on the number of lesions and was intended to help field personnel to quickly triage patients for treatment. Even if the WHO allows for initial classification without testing, it is recommended that a bacillary index is determined to ensure that patients are receiving the proper treatment. [49] Thus, a general classification of disease that combines elements of both of these systems is based on the number of skin lesions present and the number of bacilli found on tissue smears. Paucibacillary disease (indeterminate leprosy and tuberculoid leprosy) has five or fewer lesions and no bacilli on smear testing. More than five lesions with or without bacilli (borderline leprosies and lepromatous leprosy) is considered multibacillary disease. Classification may be further refined by considering other criteria, such as the number of body areas affected and the size of the largest skin lesions. [50]
Indeterminate leprosy
This early form causes one to a few hypopigmented or, sometimes, erythematous macules. Sensory loss is unusual. Approximately 75% of affected persons have lesions that heal spontaneously. In some, the disease may persist in this indeterminate form. In those with weak immunity, the disease progresses to one of the other forms.
Tuberculoid leprosy
Skin lesions are few. One erythematous large plaque is usually present, with well-defined borders that are elevated and that slope down into an atrophic center. The lesions can become arciform or annular. They can be found on the face, limbs, or elsewhere, but they spare intertriginous areas and the scalp. Lesions can be dry and scaly, hypohidrotic, and hairless. Another presentation involves a large, asymmetric hypopigmented macule. Both types of lesions are anesthetic and involve alopecia.
Spontaneous resolution can occur in a few years, leaving pigmentary disturbances or scars. Progression can also occur, leading to borderline-type leprosy. In rare instances in which a patient is untreated for many years, the lepromatous type can develop.
Neural involvement is common in persons with tuberculoid leprosy; it leads to tender, thickened nerves with subsequent loss of function. The great auricular, common peroneal, ulnar, and radial cutaneous and posterior tibial nerves are often prominent. Nerve damage can happen early, resulting in wrist drop or foot drop.
Borderline leprosy
Borderline tuberculoid leprosy
Lesions in this form are similar to those in the tuberculoid form, but they are smaller and more numerous. The nerves are less enlarged and alopecia is less in borderline tuberculoid leprosy than in other forms. Disease can remain in this stage, it can convert back to the tuberculoid form, or it can progress to lepromatous leprosy.
Borderline borderline leprosy
Cutaneous lesions consist of numerous, red, irregularly shaped plaques that are less well defined than those in the tuberculoid type. Their distribution may mimic those of the lepromatous type, but they are relatively asymmetric. Anesthesia is only moderate. Regional adenopathy may be present. Disease may remain in this stage, it may improve, or it may worsen.
Borderline lepromatous leprosy
Lesions are numerous and consist of macules, papules, plaques, and nodules. Annular punched-out–appearing lesions that look like inverted saucers are common. Anesthesia is often absent. As with the other forms of borderline leprosy, the disease may remain in this stage, it may improve, or it may regress.
Lepromatous leprosy
Early cutaneous lesions consist mainly of pale macules. Late infiltrations are present with numerous bacilli. Macular lesions are small, diffuse, and symmetric. The skin may be smooth and shiny, but skin changes do not occur in lepromatous leprosy until late in the course. Therefore, early lepromatous leprosy lesions have little or no loss of sensation, nerves are not thickened, and sweating is normal. Nerve loss is slow and progressive.
Hypoesthesia occurs first over extensor surfaces of the distal extremities, followed by weakness in the same areas.
Alopecia affects the lateral aspects of the eyebrows (madarosis), spreading to the eyelashes and then the trunk. Scalp hair remains intact.
Lepromatous infiltrations can be diffuse, can occur as nodules (called lepromas), or can be plaques. The diffuse type results in the thickened skin appearance of a leonine facies. Neuritic lesions are symmetric and slow to develop.
Eye involvement occurs, causing pain, photophobia, decreased visual acuity, glaucoma, and blindness.
Nasal infiltration can cause a saddle-nose deformity and impaired olfaction. Hoarseness ("leprous huskiness") and stridor are a result of laryngeal involvement. [51]
Oral lepromas, usually located on the hard and soft palate, uvula, tongue ("cobblestoning"), lips, and gums, can progress to necrosis and ulceration. Tissue destruction may result. [52]
Infiltration of the helix or megalobule (elongation and wrinkling of the earlobe) may occur.
Lymphadenopathy and hepatomegaly can result from organ infiltration.
Aseptic necrosis and osteomyelitis can occur with repeated trauma after joint invasion.
Brawny edema of the lower extremities is a late finding.
Unlike the other types of leprosy, lepromatous leprosy cannot convert back to the less severe borderline or tuberculoid types of disease.
Histoid leprosy
This is a recognized clinical variant of lepromatous leprosy. [53] It can occur as a result of M leprae resistance to monotherapy of MDT. Reports of de novo histoid leprosy suggest that it may also possibly evolve from borderline or indeterminate leprosy. Paucibacillary and multibacillary forms also exist. They may present as firm plaques or nodules. The lesions may occur on the thighs/buttocks, back, face, and extremities, especially bony areas like the elbows and knees. Eyebrows and nasal cartilage are usually spared.
Pure neural leprosy
This occurs in the absence of skin lesions, presenting with mononeuritis (isolated peripheral nerve involvement, including cranial nerves), mononeuritis multiplex, and polyneuritis. [54] Nerve abscesses have been reported. [55] Slit-skin smears are negative. However, cutaneous lesions may follow, which would require reclassification into one of the traditional categories listed above. [6]
Lepra reactions
Lepra reactions, including erythema nodosum leprosum (ENL), are complications that occur in 20-50% of patients after the start of therapy or occasionally before therapy (see Complications).
Complications
Reactional states occur in approximately 20-50% of patients and are acute inflammations of the disease. They may be induced by MDT, physical or mental stress, puberty, childbirth, trauma, pregnancy, or surgical procedures. A leprous reaction should be considered a medical emergency and mandates immediate care. These states can result in permanent neurologic sequelae and are the leading causes of grade 2 disability. Patients at the highest risk are those with multibacillary leprosy, those with preexisting/persistent nerve impairment, those with positive anti-PGL-I, and those with positive bacillary indexes in skin smears. [56] MDT should be continued through the reactional episode.
Lepra type I (reversal) reactions usually affect patients with borderline disease. Reversal reactions are a shift toward the tuberculoid pole after the start of therapy, and they are type IV cell-mediated allergic hypersensitivities, with CD4+ lymphocytes infiltrate lesions with high levels of IFN-gamma and TNF-alpha, indicating an improvement in cell-mediated immunity. These reactions are characterized by increased inflammation of preexisting lesions and edema of the face and extremities, with edema and tenderness of peripheral nerves. New skin lesions are common, and the patient may have an acute febrile illness. The peak time for type I reactions is during the first 6 months of therapy and for up to 12 months. Corticosteroid treatment is aimed at controlling acute inflammation, relieving pain, and reversing nerve and eye damage. With treatment, approximately 60-70% of the patient's nerve function is recovered. [57] If neuritis is absent, NSAIDs may be helpful. Skin lesions have been successfully treated with the addition of topical tacrolimus. [58]
Lepra type II reactions, or erythema nodosum leprosum (ENL), occur in approximately 10% of patients with borderline lepromatous leprosy and in 20% of patients with lepromatous leprosy. These reactions are type III humoral (antibody-antigen) hypersensitivities, with a systemic inflammatory response to immune complex deposition. The most common presenting symptoms are crops of painful erythematous nodules of the skin and subcutaneous tissue. Sweet syndrome –like lesions have also occurred. [59] Bullae, ulcers, and necrosis also may occur. [60] Nerve damage is slower than in reversal reactions. The reaction usually manifests after a few years of therapy, and, although a single acute episode is possible, relapses occur intermittently over several years. Associated fever, malaise, arthralgias, neuralgia, iridocyclitis, dactylitis, orchitis, and proteinuria may be present. The use of clofazimine in MDT substantially reduces the incidence of ENL to 5%. Clofazimine has also been used to treat ENL. Mild cases can be treated with NSAIDs. Thalidomide is effective except in the case of neuritis or iritis, in which case corticosteroids should be used. Thromboembolic events are reported with thalidomide use. [61] Other treatment therapies reported to be effective include colchicine, pentoxifylline, cyclosporine A, azathioprine, [62] methotrexate, [63] intravenous immunoglobulin, infliximab, [64] and etanercept. [65]
Lowering the dose of dapsone may decrease the severity of bullae and ulcers.
Lucio phenomenon [66] is a cutaneous necrotizing vasculitis that is sometimes designated a type II reaction. It is common in Mexico and Central America and is characterized by erythematous, geometric, irregular-shaped macules that rapidly progress to ulceration and necrosis on acral areas or extremities of patients with diffuse lepromatous leprosy. Systemic symptoms such as hepatosplenomegaly, fever, arthritis, and nephritis are usually present. Thalidomide is ineffective in treating this type of reaction; however, no consensus on treatment had been determined. [67] Most patients with Lucio phenomenon have not received MDT or were treated irregularly; therefore, MDT is recommended. Azathioprine or cyclophosphamide with corticosteroids with or without plasmapheresis has also been used.
The real challenge in managing leprosy is the treatment of reactional states.
If the course of MDT is not complete, continue taking those medications as directed.
Systemic steroids are effective in reducing inflammation and edema in reversal reactions; therefore, they are the most helpful medications in preventing nerve damage.
Prednisone at 1-2 mg/kg/d should be given until clinical improvement is seen, then tapered slowly over 3-6 months (and possibly longer). [68] One study suggests a course of at least 8 months. [69] This long course is necessary to decrease the severity of disabilities and deformities.
Clofazimine can also be used as a steroid-sparing agent for reversal reactions, alone or with corticosteroids.
Although the World Health Organization (WHO) does not support its use for ENL, thalidomide is highly effective with ENL. It is ineffective for the treatment of reversal reactions.
It is not unusual for an immunosuppressive therapy for a reactional state to cause a re-activation of a latent comorbid infection. Consider screening for chronic hepatitis B, chronic strongyloidiasis, latent tuberculosis, Chagas disease, and human immunodeficiency virus (HIV) infections before starting MDT, in patients who come from geographic areas where any of these conditions are endemic. [70]
Neuropathy induced by leprosy can result in trauma, pressure necrosis, or secondary infection that goes unnoticed, leading to amputation of digits or limbs. Wrist and foot drop are also common. Silent neuropathy can occur in the absence of overt signs of nerve or skin inflammation. Even with corticosteroid treatment, only approximately 60% of nerve function is recovered. Cyclosporine A may be useful in controlling nerve impairment and pain. [71] Intraneural corticosteroid injection in one case resulted in nerve regeneration and improved sensory and motor function. [72] Tibialis posterior transfer by the interosseus route with early postoperative mobilization can correct foot drop in leprosy. [73, 74]
Injuries can result in ulcerations, cellulitis, scarring, and bony destruction. Foot ulcers discovered early should be treated with rest because they heal if they are not subject to weight bearing.
Osteoporosis and fractures can result from bony changes due to leprosy. Risedronate and other bisphosphates may help improve lumbar bone mineral density. [75]
Contractures can develop and may result in fixation. Common sequelae include clawing of hands and feet.
Arthritis/arthralgias may occur in approximately 10% of patients with leprosy and joint symptoms, and in conjunction with reactional states. Most have polyarticular symmetric arthritis. The arthritis is generally not responsive to conventional therapy, but 50% become asymptomatic within 24 months of diagnosis. [76]
Eye damage, especially in the anterior portion of the eye, can result in loss of the corneal reflex, lagophthalmos, ectropion, entropion, and blindness. One study found the risk of ocular complications in patients with multibacillary disease, after completion of MDT, to be 5.6%, with eye-threatening complications at 3.9%.
Skin drying and fissures can be caused by autonomic disruption.
Hypogonadism and testicular atrophy can lead to sterility and gynecomastia. Testosterone replacement is the treatment of choice.
Renal involvement in leprosy, particularly lepromatous leprosy and ENL, have been described. Findings may range from hematuria and proteinuria to acute and chronic glomerulonephritis, interstitial nephritis, and pyelonephritis. [77]
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Hands with Z-thumbs, clawing, contractures, and shortening of fingers due to repetitive injury and healing. Ho Chi Minh City, Vietnam. (Courtesy of D. Scott Smith, MD)
