The majority of infections do not give rise to symptoms (only to a positive lepromine test). After infection there is an incubation period of 2-15 years (the mycobacteria multiply slowly). If the patient does not recover spontaneously, a transient indeterminate lesion appears. It consists of one or more grouped hypopigmented non-pruritic macules which are more or less well delineated. On white skin they are red or hyperpigmented. There will rarely be any reduction of sensitivity (hypo-aesthesia). Sometimes somewhat reduced sweating is seen. Nerves never become thickened at this stage. Bacilli are practically never found in this lesion. After the initial lesion there is evolution towards recovery or towards one of the forms in the spectrum TT – LL, which usually occurs within 2 years. Approximately 75% of indeterminate leprosy cases recover spontaneously. This indeterminate stage is often not diagnosed. Some leprosy infections can be diagnosed on clinical grounds alone especially in family members of an untreated leprosy patient. In other situations, diagnosis is often only possible via histology.

In tuberculoid leprosy, there are only one, or a few, asymmetrical skin spots on not more than two parts of the body. They are sharply delineated, sometimes with a slightly elevated border and central healing. There are often papules on the edge. The lesion is rather depigmented (hypopigmentation on dark skin) or erythematous (on white skin) and there is loss of sensitivity. First the sensitivity to temperature decreases, then the sense of touch, then pain and finally deep sensitivity. There is hair loss and the skin is dry. One or two peripheral nerves are affected (thickened), at the areas of predilection or in the region of the skin lesion. The consequences of neural dysfunction appear early (muscle weakness and atrophy, reduced sensitivity to pain, sense of touch and sweating). Paralysis is common. It sometimes occurs before the loss of sensitivity. There is no direct involvement of other tissues. Leprosy is the only infectious disease which causes thickening of the nerves. Purely neurological involvement also sometimes occurs, without skin abnormalities. This slow form of neural dysfunction stands in sharp contrast to the swift neurological damage which occurs during leprosy reactions. In leprosy, autonomous symptoms such as bladder or bowel problems, postural hypotension, impotence, etc are rare. Patients with amyloidosis tend to have pronounced autonomic neuropathy.

Note : Nerve thickening

Nerve thickening may also occur in rare disorders such as certain forms of primary amyloidosis of the nerves and inherited muscular and nervous diseases. Déjerine-Sottas disease is a rare form of hypertrophic neuritis which usually leads to invalidity in childhood. Here, the skin is normal. In some cases of Charcot-Marie-Tooth disease (hereditary sensomotor neuropathy type I), hypertrophic neuritis occurs. In Refsum’s disease, an autosomal recessive familial disorder, there is a defect in the degradation of phytanic acid, which sometimes causes thickening of nerves, together with cerebellar ataxia, progressive deafness, heart problems, skeletal deformations, retinitis pigmentosa and dry skin (ichthyosis). Neurofibromatosis can also be included in the differential diagnosis (including café-au-lait patches). Traumatic injury may sometimes cause local thickening, as may amyloidosis.

Patients with borderline leprosy have lesions which fall between the tuberculoid and lepromatous forms. Multiple skin lesions exist and nerve lesions are common. This is an unstable condition which will evolve to one or other of the polar forms.

There are countless disseminated macules and/or skin nodules, with blurred outlines and sometimes joining to form larger plaques. No tendency to central healing is seen and there is no hypopigmentation, although sometimes a "copper colour" is present. The infiltrated skin nodules do exhibit less or no anaesthesia, but numbness develops in the hands and feet. The skin infiltration may lead to diffuse skin thickening, chiefly of the ears, lips and forehead ("lion’s face" in LLp). In Mexico, the diffuse variety of leprosy is sometimes called "pretty leprosy" because it tends to iron out the wrinkles in the skin, restoring a youthfull appearance to the patient. Infiltration of the mucosa leads to chronic rhinitis with epistaxis, septum perforation and destruction of the nasal cartilages. The tongue is thickened and there may be hoarseness. The upper incisors become loose and often drop out. There is often loss of the eyebrows (madarosis) and eyelashes. The central portion of the forehead (frontalis muscle) is more affected than the lateral portions. This sign is quite characteristic for leprosy and was first described by Monrad-Krohn. The sensory loss on the forehead can be quite marked (since the skin is relatively cool) but at the hairline, there tends to be an abrupt increase in the sensitivity to pinprick. Testicular atrophy leads to gynaecomastia. The nerves are not severely thickened, but involvement of the nerves is extensive, generalised, gradual and symmetrical. The consequences of this loss are evident later in the disease and sensory dysfunction, rather than motor defects, are foremost. Deep tendon reflexes are preserved for a long time, which distinguishes this diseases from many other neuropathies (except amyloidosis). Vibration sense and position sense remain intact for a long time. With progression of the disease, the motor branches of small nerves are invaded, so that there is distal atrophy, especially in the hands.

Blindness occurs more often in tuberculoid than in lepromatous leprosy. Blindness may be caused by:

• Involvement of the facial nerve. This causes peripheral facial paralysis. The eye can no longer close (lagophthalmia), which leads to drying out of the cornea. The patient attempts to draw the eyes upwards under the eyelids to moisten them. The lower eyelid may exhibit paralytic ectropion. Artificial tears may prevent corneal dehydration. Sometimes the eyelid needs surgical correction to prevent blindness.
• Involvement of the trigeminal nerve leads to an insensitive cornea. The patient does not feel the dehydration or the presence of dust, resulting in keratitis. Artificial tears, as used in sicca syndrome, may be beneficial.
• Infiltration of the eye by countless bacilli with possible formation of lepromas (nodules full of bacteria). The latter obviously only occurs in lepromatous leprosy.
• Iridocyclitis, for which eye drops with steroids are indicated. Cataract formation and phtysis bulbi are late complications.
• Beware of glaucoma in patients treated with cortisone (leprosy reactions!). Topical cortisone administered as eyedrops is more dangerous than systemic cortisone.

Mutilations may occur due to:

• Paralysis with muscular atrophy and contractures.
• Loss of sensitivity leads to not noticing wounds or burns and maintaining postures which would otherwise be painful.
• Failure of autonomous nerves resulting in trophic skin disturbances.
• Untended wounds with secondary infections may lead to chronic ulceration. Tissue destruction and bone resorption lead to mutilation of the fingers, hands, toes and feet. Most mutilations can be avoided.
• Direct destruction of tissues, e.g. the nose. Bone lesions in LL are often more attributable to direct destruction than due to bacterial infiltration. Injuries are made worse by anaesthesia, superinfection, atrophy and ankylosis following disuse. The phalanges of fingers (dactylitis) and toes are most frequently affected, shorten gradually and become thinner due to lateral bone resorption.

The host’s immune responses to the leprosy bacillus create some of the pathology associated with the disease. Unfortunately, and confusingly, the classification of the clinical (Arabic) and immunological (Roman) reactions use different numbering systems. Beware: A leprosy type 1 reaction has nothing to do with the hypersensitivity-anaphylactic type I reaction.

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Lesions caused by a change in the immunologic defence of the patient are called type 1 reactions. These reactions may triggered by treatment, by pregnancy or is sometimes due to spontaneous changes in immune defence. Polar forms are generally immunologically stable and do not develop type 1 reactions. In the central part of the clinical spectrum there are fluctuations in the number of bacilli and in the patient’s resistance. If the patient’s immune defence increases, many leprosy bacilli will be destroyed. The body may react strongly to proteins released from these dead bacilli. This type of reaction (previously called an upgrading reaction) may cause damage to the body itself. Existing skin lesions become inflamed, discoloured red and painful. [Signs of inflammation of the leprosy patches are only found in leprosy reactions]. There will rarely be new lesions. Paralysis may occur quickly. Treatment of such a reaction must be swift to limit the damage: anti-inflammatory therapy (aspirin, indomethacin, corticosteroids), immobilisation of the affected body part. The leprosy therapy is not discontinued.

Sometimes the immune response may be reduced. Nowadays this is seldom seen. Progressive leprosy lesions develop (previously called a downgrading reaction). They take a less dramatic course than upgrading reactions. The treatment is swift adjustment of the leprosy therapy.

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Patients with LL have almost no cellular defence against the leprosy bacillus. They do produce many antibodies, but these are not protective. The antibodies may precipitate in the body in the form of immune complexes and cause a different set of lesions (type III hypersensitivity reaction). This type of reaction is called a type 2 leprosy reaction. It is also called Erythema Nodosum Leprosum (ENL). ENL shows a high relapse tendency. Leprosy reactions are an important cause of mutilation. These reactions appear as sudden new red painful skin nodules on the legs and arms, which may form sterile pustules or ulcers. The symptoms are usually generalised, such as fever and general malaise, accompanied by muscle and joint pain, proteinuria, inflammation of the eyes and swelling and pain in the nerves, acute epididymo-orchitis. Approximately half of LL and BL patients develop ENL a few months after beginning chemotherapy. Patients with TT are spared this complication. Differentiation between type 1 and 2 reactions is not always easy.

The treatment of ENL consists of analgesics, clofazimine at higher doses than normal leprosy therapy (300 mg/day for 1 to 3 months) but it is a slow-acting drug, corticoids systemically and if necessary eye drops. If needed the fast-acting drug thalidomide can be used (Softenon®, 100 to 400 mg/day for 10 days, then reduced to 50-100 mg daily). Thalidomide is not an immunosuppressive, but what is called an immune-modulating drug. It changes the balance of a number of cytokines. For example it is an antagonist of TNF-alpha and increases the action of IL-2. Contraception is absolutely essential during the use of thalidomide, since it is highly teratogenic (probably due to interference with angiogenesis in the foetus, not due to induction of mutations). Thalidomide may itself trigger peripheral neuropathy.

Cyclosporin A (Sandimmun®) is a cyclic polypeptide with immunosuppressive properties which may be beneficial in type 2 reactions. It blocks helper T-cell activation. [Cyclosporin was originally isolated in 1969 from a Norwegian soil fungus, Tolypocladium inflatum. Since 1996 it has been known that the sexual form of this fungus (Cordyceps subsessilis) occurs in nature as a pathogen of dung beetles]. Nephrotoxicity is an important dose-dependent, and usually reversible, side effect of this product and occurs in 25-75% of patients. Neurotoxicity (tremor), hirsutism and gingival hyperplasia also occur. The drug is embryotoxic in animals. Do not confuse cyclosporin with cyclophosphamide or cycloserine. Unlike some other immunosuppressive agents, there is no myelodepression with this drug.

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