International journal of Dermatology, Vol, 34, No, 2, February 1995

REVIEW

POST-KALA-AZAR DERMAL LEISHMANIASIS

V. RAMESH, M.D,, AND A, MUKHERJEE, M,D,

Post-kala-azar dermal leishmaniasis (PKDL) is a dermato-sis described during the first quarter of this century andalmost confined to the countries on the Indian subconti-nent. It is uncommonly seen in certain parts of Africa. InIndia it generally follows an attack of kala-azar (KA) andappears to be a dermal extension of the disease, mani-fest after months or several years of treatment of KA.The disease is characterized by a widespread eruption oferythematous papules, hypopigmented macules, andnodules, but unusual variants may be seen. The lesionspersist for long periods and complications can resultwhen mucous membranes are affected, the most seriousbeing blindness due to corneal involvement.

Histopathologically, a polymorphic infiltrate ofmacrophages, plasma cells, and lymphocytes is seen.The detection of Leishman-Donovan bodies in themacrophages is pathognomonic. The pathogenesis ofPKDL remains obscure. The pentavalent antimonialsstill remain the treatment of choice.

HISTORICAL OVERVIEW

Even before the discovery of the parasite Leishmaniadonovani in 1903,^'^ the name 'kala-azar' (KA) or blacklever was aptly coined for an illness that raged acrossthe eastern part of India in epidemic outbreaks duringthe latter half of the 19th century. The word 'kala' signi-nes both the dark color and a dark future.'' Intensesearch and trials led to the effective introduction of anti-monial compounds to control KA. It was Brahmachari in1922'* who first described in a meeting of the Asiatic So-ciety of Bengal four patients with eruptions and plaquesafter 6 months to 2 years of treatment for KA. Leishman-Donovan bodies (LDB) were demonstrated by slit-skinsmears and hence termed dermal leishmanoid. Soon theterm Brahmachari's dermal leishmaniasis was suggestedto avoid confusion with other types of leishmaniasis,'but doubts remained, whether the organisms were thesame that caused KA, because the manifestations were souifterent. The similarity was experimentally proved*-^and because the eruptions followed KA, it was renamedpost-kala-azar dermal leishmaniasis

rom the Department of Dermatology and the Institute ofPathology (ICMR), Safdarjang Hospital, New Delhi, India.

Address for correspondence: V.Ramesh, M,D., Sector 12/1082,RK Puram, New Delhi-110 022, India,

ETIOLOGY

The organism Leishmania donovani is a viscerotropicflagellate protozoon, morphologically indistinguishablefrom those that cause cutaneous leishmaniasis. In hu-mans and animals the parasite is seen in the amastigote(or leishmanial) form, whereas the flagellate (or lep-tomonad) form occurs in the insect vector, the sandfly.Subtle biochemical and seroiogic differences have iden-tified three subspecies in the L donovani species com-plex: L. donovani donovani, L.d. infantum, and L.d.chagasi. L.d. donovani is responsible for KA in Indiaand neighboring countries.

GEOGRAPHIC DISTRIBUTION

In India, after the first report from Bengal,'' PKDL wassubsequently documented from other areas.'"'^ Exten-sive investigation disclosed no animal reservoirs, indicat-ing that KA was confined to humans. In the early nine-teen hundred sixties, a decline in PKDL was observed,after effective antimalarial campaigns brought aboutgood vector control," but a slackening of this controlwas followed by a resurgence of KA;''' currently it is rifein the states of Bihar and West Bengal.'^ The othercountries, where PKDL is seen are Bangladesh, Nepal,and Pakistan."" Apart from the countries in the Indiansubcontinent, PKDL has also been reported from China""and Iraq,'* but is infrequently seen in Africa, where itgenerally occurs as a transient rash toward the end orsoon after therapy for KA.''-̂ " Few reports of PKDL simi-lar to the Indian variety have been described.̂ ^-^^

INCIDENCE

The incidence of PKDL generally runs parallel to that ofKA and is in direct proportion to the chronicity of theinfection in the locality.^^ In one major center, the inci-dence fell from 0.32% in 1954 to 0.025% in 19642'*after, good vector control. Currently, it is again on therise, as seen from a recent survey from an endemic areawith prevalence rate of 4.82/1000."

CLINICAL EEATURES

Although KA and PKDL are caused by the same organ-ism, they differ considerably in their sites of predilec-

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tion and response to therapy. Thus it would be interest-ing to note the skin involvement in KA, in which mainlythe viscera are involved. These are given in Table 1 andnonspecific symptoms predominate. As KA progresses,there are signs of anemia, anasarca, and rarely jaun-dice. Loss of subcutaneous fat may lead to markedwasting and prominent veins. An earth-grey pigmenta-tion is seen in the early stages,̂ *" whereas tbe typicalblackening seen in chronic cases is said to be commonin Assam,^^ where the term KA was coined. The pig-mentation is most evident on the forehead, temples,and occasionally tbe perioral area. It is less marked inwhite people, but marked in dark-skinned persons, in-tensified by contrast with the pallor of the rest of theface.^^ Wasting, bleeding episodes such as epistaxis,and secondary skin infections are usually seen in infan-tile KA. Specific skin lesions have rarely been reported inIndian KA,̂ '̂̂ ^ but is more common in KA seen else-where.''>•"' Healed chancres or nodules resulting fromthe bite of a sandfly are generally absent or very tran-sient.^^ A report of KA presenting as a nasopbaryngealmass is noteworthy.^^ Leishman-Donovan bodies havealso been demonstrated in nasal secretions^^ and rarelyin apparently normal skin,^* accounting for their occa-sional presence in nonspecific ulcers seen in KA.̂ ^

Post-kala-azar dermal leishmaniasis is the most im-portant sequela seen in 5-10% of patients who havebeen treated and declared cured of KA. In 15-20% nopreceding history of KA is available suggesting subclini-cal infection and tbe fact that Brahmacbari's diseasewould be an appropriate name. The best descriptionsbave been recorded in the early half of this century,when therapy for PKDL was unsatisfactory and the dis-ease could be observed for long periods. The diseaseusually occurs 1-2 years after recovery from KA,** butmay occur much later. It is seen mostly in persons be-tween 20 and 40 years of age, and occurs eitber equallyin both sexes or more frequently in men; the prevalencebeyond 40 years and in cbildren less than 10 years isvery low.''' Studies from endemic areas on large seriesof patients '̂*'-''*'̂ ^ and by others on a smaller

Table 1. Cutaneous Manifestations of Indian Kala-azar*

Nonspecific ManifestationsDry, rough and hard skin with an earthy-grey hueUlcersHemorrhagesPigmentationEruptions including bullous lesionsStomatitisCancrum orisSecondary skin infections and infestationsSparse, lusterless, and brittle hair

Specific Skin LesionsPapules and nodulesNasopharyngeal tnasst

''From Ref. 26-28; tfrom Ref. 32.

reveal three main lesions that can be seen, of which 1or 2 may predominate:

(1) Erythema and induration typically commence ontbe butterfly area of the face, being transient andrnaximal during midday suggesting pbotosensi-tivity. Later it becomes permanent. Tbe tiose,cbeeks, and chin are affected, the outer aspects ofthe face and ears being generally spared. Tbetrunk and extremities are also involved. Tbis ery-tbematous induration described by some asbrownish discoloration''-^ should not be mistakenfor byperpigmentation that is not a feature ofPKDL. Rarely erythema can be extensive, resem-bling erythroderma.'"^

(2) Hypopigmented macules that initially start aspin-point lesions and gradually attain a size notlarger than 1 cm and with irregular margins.They are multiple and form large figurate areasby coalescence leaving islands of norrnal skin(Fig. 1). They tend to be symmetric and their dis-tribution is generalized or localized to the extrem-ities or trunk. The sites affected in the order ofpreference are: upper trunk, arms, forearms,thighs, legs, abdomen, and neck. Tbe bypopig-mented macules are scattered over the abdomen:on the back tbe interscapular and the midlineareas escape until late in the disease. The belt-area of the abdomen'" and tbe opposed surfacesof the axillae and groins often retain their normalcolor (Fig. 2). The hypopigmentation can be ex-treme, resembling vitiligo. Tbis is probably whythey are called depigmented in the earlier litera-ture. Unlike vitiligo an acral distribution involv-ing the face, hands, and feet is unusual.

(3) Papules and nodules arising in the affected areas orfrom apparently normal skin. Typically the fore-head, chin; and muzzle areas of the face are affect-ed (Fig. 3). Diffuse enlargement of the nose may re-sult from coalescing lesions. At times lesions maybe scattered on tbe wbole face. Tbe trunk and ex-tremities can be affected, the genitalia being a fa-vorite site. Linear indurated plaques, streakingalong the creases of the axillary folds and buttocks,may be seen. Tbe nipples can be involved.''^ Withtime the nodules enlarge (see Fig. 1) and form bigplaques but do not tend to ulcerate.

The unusual variants of PKDL include^''''"'''*'' tbe an-nular type, hypertrophic forms such as warty or papil-lomatous growths, and presence of lesions in uncom-mon sites such as eyelids, palms, the perionychium.Another uncommon variety is the fibroid type ofPRDL''"" characterized by erytbematous plaques on thedorsa of fingers and toes resembling knuckle pads.Rarely, a xanthomatous transforrnation is seen inchronic nodules, simulating xanthoma tuberosum.*"

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Figure 1. Islands of normal skin and a big nodule within alarge hypopigmented area.

Mucous membrane involvement is usually seen onthe borders of the lips and at times elsewhere. Theselocations include the glans penis, tongue, inner aspectof cheeks, and the hard and soft palate."•""•'"'^^ Scleralnodules and keratitis can also occur.''*' Restriction ofPKDL only to mucosal sites with destructive lesions inthe nasal septum, oropharynx, and even the larynxhave been documented.^-' Esophageal involvement hasalso been observed.^''

been suspected, '̂*'̂ '' is a moot question. Compared toKA,̂ *" the danger of intrauterine transmission to thefetus is unlikely, because PKDL is restricted to the skin,but if lesions are present on the nipple, the remote pos-sibility of acquiring the infection by the suckling infantcannot be ruled out. The greatest danger is to the com-munity, because all types of skin lesions are a potentialsource of infection.-^-'

HISTOPATHOLOGY

""** and later '̂̂ " '̂ studies have revealed that thegranuloma comprises mainly lymphocytes, macro-phages, and plasma cells in varying proportions. It isminimal and confined to the perivascular areas in hy-popigmented macules and more dense occupying theentire dermis in nodules and plaques. The macrophageslie scattered in the infiltrate. A recent histopathologicstudy" reveals, that the predominant cellular pattern isthe one described above showing sparse LDB; the un-common variants showing macrophage granulomasand numerous LDB, and some with epithelioid or sar-coid-like granulomas develop in advanced nodular le-sions. In chronic nodules, there is a general increase ofreticulin fibers arranged in a uniform honeycomb pat-tern" and perivascular fibrosis is marked.-'' Russellbodies may be seen in the large collections of plasmacells.*̂ ^ The xanthomatous forms show more fibrosisand there is constriction of the venules with subse-quent dilatation accounting for the deep orange-redhue.** A definitive diagnosis rests upon the demonstra-tion of LDB within the macrophages. They are found

COURSE OE PKDL AND COMPLICATIONS

The temporal evolution of the lesions in PKDL has beenexplained in various ways. Some feel, that the hypopig-mented macules are first to appear, followed by papulesand nodules that persist longer than 30 years;''' othersfeel that erythema precedes all manifestations.'" Bothmay be true in patients, in whom the parasites are al-ready present in the apparently normal skin and it isnot possible to predict the precedence of a lesion with-out a good understanding of the subtle host-parasite in-teractions. The unusual instances of ulceration havebeen due to treatment with iodides,̂ ** trauma,^" andmucosal stretching by the expanding granuloma.-"''"' Insome ulcers, no specific cause could be attributed.^^'"

ost-kala-azar dermal leishmaniasis is known for itschronicity without leading to any complications. A seri-ous, but rare, complication is blindness due to cornealinvolvement.'* Laryngeal lesions lead to dysphonia.-'^^here is evidence that the disease may be transmittedsexually, when the genital mucosa is affected." WhetherPKDL causes KA in the same person that has occasionally

Figure 2. Hypopigmented macules on trunk, sparing the in-terscapular, midline, and belt areas.

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i

Figure 3. Papules and nodules in the erythematous centralpart of the face.

with greater frequency and number in nodules andplaques. It is not always possible to demonstrate LDB,because even in ideal situations is the success rate only58%.^^ This can be partly overcome by using iron-hematoxylin stain in place of hematoxylin and eosinand Ciemsa stains for locating LDB,̂ ^

The absence of LDB is difficult to explain. It may berelated to the intradermal leishmanin test, the negativeones being more likely to show LDB than the positive.Another reason could be the good host-parasite rela-tionship that allows the organism to lie dormant, untilconditions favor its multiplication. This is supportedby the observation, that the macrophages showed nostructural evidence of activity to the presence of LDBwithin them,̂ -̂ The demonstration of LDB within thenerves in African PKDL*'' is a feature not seen in Indianforms until now.

The epidermal changes are insignificant except forreduced pigment in the melanocytes in hypopigmentedmacules,^^ and indurated lesions may show Pautrier-like abscesses with intracellular edema and hydropicdegeneration.^''

DIAGNOSIS

The diagnosis of PKDL rests on the demonstration ofLDB in slit-skin smears. A notable fact is that the extentof skin lesions is not always proportional to the num-ber of organisms." Culture in blood-agar-based mediais recommended on other occasions and in those withhypopigmented macules where slit smears are oftennegative.

The intradermal leishmanin or Montenegro testmay or may not be positive, Seroiogic examination re-veals nonspecific findings.''^ In those, in which no LDBare seen or are not positive on culture,^" the diagnosisof PKDL hinges on the endemicity of KA in the area, rul-ing out other disorders, and on the response to antimo-nial therapy.

DIFFERENTIAL DIAGNOSIS

The disease with which PKDL has often been confusedis leprosy. The salient features differentiating themhave been enumerated in detail,^'' A history of KA, clus-tering of lesions in the central part of the face, and thepresence of islands of normal skin and papules or nod-ules within hypopigmented areas point towards PKDL.

Other disorders simulating PKDL include: diffuse cu-taneous leishmaniasis, secondary syphilis,^''^' and sar-coidosis.^^ When the papules are localized on the face,the possibility of rosacea^^ and photodermatoses shouldbe kept in mind. In those with macuies, pityriasis versi-color,''^ and vitiligo should be ruled out. Lesions con-fined to nasal and oropharyngeal areas can mimic in-fections,^^ such as lupus vulgaris and rhinoscleroma,and other tumors.

PATHOGENESIS

The pathogenesis of PKDL is one of the most interestingaspects of the disease. It has been observed that L.donovani, unlike L. tropica, can remain localized tothe skin without producing any lesions,'* indicating ei-ther a carrier**^ or exovisceral phase of the parasite.'**The fact that LDB are rarely demonstrable in the skin inKA is consistent with the observation, that only 5-10%develop PKDL. In sharp contrast is the observation, thatPKDL is rare in other areas, where a larger number ofKA patients show the presence of LDB in the affectedand apparently normal skin. Furthermore, the skin isnot a preferred site^' and is even said to be a barrieragainst any form of leishmaniasis.^* Thus PKDL seen inthis subcontinent is a unique example of adaptabilityof the parasite to the host in the absence of a zoonoticreservoir. The possibility that PKDL arises from reinfec-tion in a person, who has acquired visceral immunityfrom a past infection, is evidenced by a reduced inci-dence after good vector control.^^

Dermal LeishmaniasisRamesh and Mukhenee

The several factors to explain Iysosomal residenceof the parasite within the macrophage have been re-viewed.''^''''' Studies on cell-mediated immunity (CMi)reveal, that PKDL is unresponsive to the specific antigenof L. donovani in contrast to the generalized immuno-suppression in KA.̂ ' This is variable and related to du-ration, since newly acquired PKDL exhibits better CMlresponse than chronic PKDL,^^ however, the develop-ment of a positive CMl response after clinical cure in KAdoes not seem to confer protection against dermal in-fection.^^ It also appears that restoration of leishmaninpositivity after a clinical cure of PKDL takes longer thanthat of in vivo tests.^''

A point that deserves mention relates to the thera-peutic response. Skin lesions disappear quickly withtreatment, when they occur as part of the syndrome ofKA and in PKDL without a definite history of KA,'* butin typical PKDL with a good cellular response, therapyof a much longer duration is required,^^ indicating thatsome organisms that were not killed and were relative-ly resistant to conventional doses of antimony used inKA, sheltered in the dermis.''' This can be proved if or-ganisms from the skin of both KA and PKDL are cul-tured and compared for their biochemical propertiesand in vitro drug response. This is also supported bythe fact that KA resulting from visceralization of the or-ganisms from PKDL in the same person as expected re-sponds poorly to treatment in KA.̂ ''-̂ ' Conversely, spreadof infection from PKDL may partly be responsible forthe enhanced dose of antimonials required in slow re-sponders of KA.̂ ^

TREATMENT

Throughout the literature, the point common to all re-ports is the refractoriness of PKDL to therapy. Evenwhen the incidence of KA was controlled, this controlWas reduced by the unsatisfactory treatment availablefor PKDL.'̂ -''*' The development of an adequate dose ofantimony and attempts to use other drugs to expeditecure have recently been reviewed.^^ The current recom-mendation of the World Health Organization (WHO) is20 mg/kg of sodium antimony gluconate (SAG) up to amaximum of 850 mg/day, given intramuscularly for 4months."" Occasionally, treatment may have to be pro-longed for up to 5 months." The intravenous routehas rarely been used to hasten regression.^''^^ Aftertreatment with SAG, the specific unresponsiveness to L.donovani antigen gradually disappears.^' Antimonymay be combined with ketoconazole or allopurinolgiven orally to improve the response, and in resistantcases amphotericin B is an excellent alternative.^^ Thehypopigmented macules persist for a long time aftercompletion of therapy. Eventually they fade and thiscan be hastened by giving oral psoralen followed bysun exposure (PUVASOL) as advised for vitiligo.

DRUG NAMES

allopurinol: Lopurin, Zyloprimamphotericin B: Eungizoneketoconazole: Nizoralsodium antimony gluconate B.A.N.

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71. Neogy AB, Nandy A, Hastidar BG, Chowdhry AB.Modulation of the cell-mediated immune response inkala-azar and post-kala-azar dermal leishmaniasis in re-lation to chemotherapy. Ann Trop Med Parasitol 1988;82:27-34.

72. Haldar JP, Ghose S, Saha KC, Ghose AG. Gell-mediat-ed immune response in Indian kala-azar and post-kala-azar dermal leishmaniasis. Infect Immun 1983; 42:702-707.

73. Haldar JP, Saha KG, Ghose KG. Immunological profilesin Indian post-kala-azar dermal leishmaniasis. In: HartDT, ed. Leishmaniasis. The current status and newstrategies for control. New York: Plenum 1989: 387.

74. Neogy AB, Nandy A, Ghowdhury AB. Leishmanin testin post-kala-azar dermal leishmaniasis. Trans R SocTrop Med Hyg 1990; 84:58.

75. Thakur GP, Kumar M, Kumar P, et al. Rationalisationof regimens of treatment of kala-azar with sodium sti-bogluconate in India: a randomized study. BMJ 1988;296:1557-1561.

76. Sen Gupta PG. Kala-azar. Bull Gal Sch Trop Med 1957;5:106-108.

77. Ramesh V. Treatment of post-kala-azar dermal leish-maniasis. Int J Dermatol. (In press)

78. Munro DD, Du Vivier A, Jopling WH. Post-kala-azardermal leishmaniasis. BrJ Dermatol 1972; 87:374-378.

General Paresis

During the nineteenth century, general paresis of the insane emerged as a newpsychiatric disorder that was extremely common and completely devastating. Al-though retrospective studies have found earlier instances of what may have beenthe same disorder, the first clearly identified examples of paresis among the in-sane were described in Paris after the Napoleonic Wars. General paresis mostoften struck people between twenty and forty years of age (men far more fre-quently than women). Within a period ranging in length from months to a fewyears after the appearance of the first symptoms, it reduced its victims to a stateof dementia and profound weakness. No treatment was known, and patients uni-formly died. During the nineteenth century the prevalence of the disorder came tobe widely recognized. By 1877, for example, the superintendent of an asylum formen in New York reported that in his institution this disorder accounted formore than 12 percent of the adtnissions and more than 2 percent of the deaths. Inthe twentieth century, with the development of accurate diagnostic methods, gen-eral paresis was definitively linked to syphilis; and with the development of effec-tive treatment methods for syphilis it has become rare.

Though historians have recently effectively applied social, political, and econom-ic analyses to psychiatry's past, they have largely ignored the history of generalparesis. When they have discussed this disorder, they have treated it as an exampleof psychiatry's success in defining and explaining disease. The history of generalparesis of the insane is, however, richer in historical ironies and more revealing ofsocial and intellectual conflicts than such accounts suggest. Erwin Ackerknecht, forexample, has noted that though Antoine-Laurent-Jesse Bayle's "discovery of pro-gressive paralysis as a separate disease picture [in 1822]...was of immense impor-tance," Bayle was nonetheless "caused to leave psychiatry altogether."

Why was there such a contrast between Bayle's fate and the ultimate glorifica-tion of his discovery? For some, such as Jacques Postel and Rene Semelaigne, thisquestion does not arise because they deny that Bayle was "caused to leave psychia-try." Instead they argue that Bayle was never seriously interested in psychiatry andthat he left the field at the first opportunity. This view is, however, implausible.Though Bayle may never have had an interest in treating the mentally ill, he was adedicated researcher. As such it is hard to imagine him abruptly and voluntarilyabandoning a field in which he had just made what he regarded as an epochal dis-covery. Further, as Semelaighe noted, Bayle always followed debates over generalparesis and was always ready to defend his priority in the discovery of that disorder.From Brown EM. French psychiatry's initial reception of Bayle's discovery of gen-eral paresis of the insane. Bull Hist Med 1994; 68:235-253.

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