248 Diffuse leprosy of Lucio and Latapi - LEPRA Health in Action

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Table 1. Presence of Mycobacterium leprae in different structures of the skin in the 200 cases of this study Structure Cases with the structure present in sections Percentage Diffuse leprosy of Lucio and Latapí 257 Cases with M. leprae in the structure Percentage Epidermis: 200 100 3 1·5 Basal cells 200 100 3 1·5 Melanocytes 200 100 2 1 Spinous cells 200 100 2 1 Granulous cells 200 100 1 0·5 Corneocytes 200 100 1 0·5 Hair follicles 102 51 47 46 Sebaceous glands 81 40,5 6 7·4 Pilli-erector muscles 101 50,5 51 50·5 Sweat glands 155 77,5 12 7·7 Nerves 43 21,5 40 93 Lymp vessels 23 11·5 15 65·22 Blood vessels 200 100 100 100 occurs, suggesting that the colonisation of the endothelial cells by acid-fast bacilli could be responsible for this damage. At the early stage, the changes consist of dilated vessels, angiogenesis, and congestion. Endothelial bacillation varies considerably with the progression of lesions. In the beginning, there are very few bacilli in the endothelial cells of large blood vessels. As time goes by, organisms increase within the endothelial cells. Later, bacilli spread progressively from the deep plexus to mid and small-sized vessels of the dermis and subcutis to give rise to a well-developed histological lesion in which most of the sections show all blood vessels having a bacillated endothelium, a finding already reported by Martinez-Baez, who said: “: ::every time one sees the picture of a blood-vessel, one can observe that the mentioned bacilli are present in one or more to the endothelial cells”. 4 The presence and constitution of the infiltrate were variable and did not seem to be related to the age of the lesion. Biopsies of some patients at a well-developed histological stage and with a long clinical evolution up to 10 years showed only a slight perivascular mononuclear infiltrate, while other cases with well-developed histological lesions but with a short clinical history showed a dense mononuclear infiltrate. Relatively few Virchow-cells were seen compared with the great number of bacilli. The fourth stage of ischaemic necrosis due to non-inflammatory vascular occlusion is characterised histologically by the presence of necrotic cutaneous lesions due to vascular occlusion by endothelial proliferation or thrombosis, and clinically it coincides with the appearance of discrete purple-coloured painful spots, which lead to ulceration of the skin without systemic symptoms. It should be stressed that the fourth stage of ischaemic necrosis due to non-inflammatory vascular occlusion seems to be caused by vascular injury induced by invasion of the endothelial cells by Mycobacterium leprae 15,16 and that tissue necrosis is due to vascular occlusion by proliferative endothelium or thrombosis. At this stage systemic symptoms do not develop and these are the cases that do not respond to thalidomide. This pattern, the damage of which is seen with or without sparse inflammatory cells, seems to correspond to the one that Rea used the term vasculosis. 28 The fifth stage of ischaemic necrosis appears as an acute reactional state that may supervene in such patients and aggravates the existing vascular damage. It is manifested microscopically by necrosis of the superficial dermis and epidermis, leukocytoclastic
258 vasculitis in small blood vessel of the dermis and of the subcutis, and lobular panniculitis. Mid-sized and large blood vessels show intimal proliferative thickening, a narrow vascular lumen, and walls infiltrated by neutrophils and lymphocytes. The fifth stage of ischaemic necrosis is considered here as a severe variant of ENL. 29 When this happens the clinical disease is exacerbated; the number of spots increases suddenly in several parts of the body, the pre-existing necrotic cutaneous lesions become aggravated and systemic symptoms appear. It is suggested that ENL and Lucio’s phenomenon may result from similar immunological mechanisms, 10 both show immune-vasculitis resulting from deposits of complement-fixing immune complexes in small blood vessel walls, 17,29 and both are may respond to thalidomide. In patients with either ENL or Lucio’s Phenomenon, deposits of IgG and C3, as well as circulating immune complexes have been found in the wall of small blood vessels. 17 It is known that immune complexes activate the complement system and become chemotatic for neutrophils, which ingest the immune complexes 30 and are subsequently destroyed in the form of nuclear fragmentation. Activation of the clotting system results in the conversion of fibrinogen to fibrin. The histological picture shows neutrophils, nuclear dust, and fibrin in the wall of small blood vessels, features that establish the diagnosis of leukocytoclastic vasculitis (LCV). 31 Clinically different manifestations are described to LCV, including macules, papules, nodules, vesicles, bullae, and ulcers. 32 Some immunological, histological and clinical aspects distinguish Lucio’s phenomenon from ENL. Immunologically, Lucio’s phenomenon occurs in patients considered the most anergic of the all-immunological spectrum of leprosy. Histologically, Lucio’s phenomenon starts with heavy colonisation of the endothelial cells by acid-fast bacilli. It develops in a tissue that already has severe vascular damage, and it is always associated with skin necrosis. Clinically, Lucio’s phenomenon is an erythema necorcitans, characterised by red and painful spots (manchas) that progress to necrosis and ulceration leaving atrophic stellar scars, occurring in a skin with diffuse generalised infiltration and complete absence of nodules, and appearing in untreated patients. In this study, one case of granulomatous vasculitis in the subcutis was only observed in patients in this stage; a change that could contribute to anoxia. 12 Another noteworthy fact, in stages four and five, was the finding of vascular occlusion by thrombi, with no signs of perivascular inflammation. The endothelium has on its surface a number of anticoagulant and procoagulation properties which, when perturbed, may lead to intravascular coagulation. 33 Therefore the activation of the endothelial cell by organisms can trigger a cascade of events leading to the conversion of fibrinogen to fibrin intravascular and thrombosis that occlude arterioles and capillaries. 34 – 36 Lucio and Alvarado remarked in their work that in these patients the level of fibrin was always elevated, and the patients bleed less during a surgical amputation. 2 The nasal mucosa is involved early in the course of Lucio’s leprosy 2 and at least 95% of all patients with lepromatous leprosy have nasal involvement too. 37 Leprosy bacilli may spread though the bloodstream from the nose to another area of the body, among them the skin. 38 – 41 F. Vargas-Ocampo The results of this study support the hypothesis that in Lucio’s leprosy there are leprosy bacilli in endothelial cells throughout the vasculature that promote the liberation of substances by the endothelium that induce vascular reactivity as manifested by distended vessels, morphological changes of the endothelial cells, areas of passive venous congestion and foci of intravascular clotting, which proceed to disseminated intravascular coagulation (DIC). DIC is one of the causes of death among these patients. 14,21,22
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248 Diffuse leprosy of Lucio and Latapi - LEPRA Health in Action

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