INTERNATIONAL JOURNAL OF LEPROSY^ Volume 54, Number 4

Printal in the U.S.A.

BOOK REVIEWS

Balakrishnan, S. Biochemical Aspects ofLeprosy (Erwin Stindl Memorial Ora-tion, 1986). Calcutta: Greater CalcuttaLeprosy Treatment and Health Educa-tion Scheme, 1986. Softbound, 40 pp.,US$3.

In recent years there has been a resur-gence of interest in the biochemistry of lep-rosy, especially that of the causative agentMycobacterium leprae. In the booklet,"Biochemical Aspects of Leprosy," Dr. Ba-lakrishnan [Assistant Director (Biochem-istry), Central Leprosy Teaching and Re-search Institute, Changalpattu, India]discusses studies on "chemical-pathologicalchanges" in leprosy patients, biochemistryof Al. leprae, as well as the metabolism ofdapsone and other drugs used in the treat-ment of the disease. Although the author'sapproach is eclectic rather than being ex-haustive, he gives a balanced appraisal ofavailable information in the field.

The first section of the review deals withliver function, renal involvement, musclefunction, connective tissue metabolism andalso serum proteins, lipids, enzymes, hor-mones and minerals in the patients. One isconstrained to say that, despite being im-portant, all these massive data have notcontributed significantly to the manage-ment of the disease. The second section ofthe booklet is devoted to the biochemistryof M. leprae. Among other things, it in-cludes chemical composition of the bacte-rial cell wall, phenolic glycolipid present inthe organisms separated from infected tis-sues, and various enzyme activities detectedin AI. leprae preparations. The substitutionof alanine by glycine in the cell wall wasconsidered to be unique to the bacilli. How-ever, David and Rastogi questioned thisfinding in a later report, and attributed it tocontamination of the bacterial suspensionsby host tissue. Dr. Balakrishnan notes thatoxidation of DOPA is the only metabolicactivity so far found to be specific for ill.leprae. The late Professor L. Mester of Parissynthesized a presumed DOPA antagonist,deoxyfructoserotonin (DFS). Studies by Ba-lakrishnan and others showed that the com-pound suppressed the growth of M. leprae

in mouse foot pads, and prevented the up-take of DOPA by the bacteria. Clinical trialsof DFS in West Africa are said to have pro-duced promising results. The metabolismof dapsone is covered in the last section ofthe review. Dr. Balakrishnan has done ex-tensive studies in this field. He has devel-oped a simple spot test for monitoring theintake of dapsone by the patients, which isquite useful, under the field conditions pre-vailing in the endemic countries.

The booklet contains a few minor print-ing errors. Although one would have wishedfor more, Dr. Balakrishnan deserves creditfor giving an overall view of an interestingfield of leprosy research in this booklet. —K. Prabhakaran

Groenen, Guido. La Lepre. Manuel Pra-tique pour les Services de la Lepre sur leTerrain. Brussels: Les Amis du PCreDamien, 1984. Softbound, 187 pp., inFrench.

Effective integration of leprosy controlinto the general health service in Zaire—asin other countries in Central Africa—hasbeen hampered by the paucity of goodteaching material in the working languageof the area, French. Dr. Groenen's manual,La Lepre, has done much to remedy thisproblem.

La Lepre is, as its subtitle implies, a prac-tical manual for field workers in leprosy. Itis written simply and clearly in French thata high school student—the reading level at-tained by most health center nurses inZaire—can understand, yet it is compre-hensive enough to be of value to a non-specialist physician. The book is well orga-nized, well illustrated, and well cross-referenced. Each chapter ends with a briefsummary of the topic covered.

The nine chapters deal with all aspects ofleprosy, from diagnosis through treatment,rehabilitation and organization of a leprosyservice. Dr. Groenen's manual is written forfield workers who may not have ready ac-cess to higher authority when faced with acase management problem. The book istherefore comprehensive, describing clearlyand simply the problems commonly en-

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54, 4^ Book Revielt's^ 665

countered in leprosy and describing how theyshould be handled. "Refer to hospital" nev-er appears as the sole solution to a problem.In Zaire it is almost never a practicable so-lution.

The annexes provide useful informationin more concise form, dealing with suchproblems as the classification of deformity,the eye in leprosy, microscopy, record keep-ing, and filling out reports.

The manual does have its shortcomings,most of them typographical. A four-pageinsert entitled "Errata" covers most of these.There are a few other errors, probably ofauthor origin. The only really dangerouserror in the book is the drawing (page 121)depicting the application of the moldeddouble-rocker plaster shoe. If applied asshown the shoe would cause an ulcer ratherthan cure one (Joseph, ei al. Leprosy Re-view 54:39-44). Perhaps an error of omis-sion occurs in that the currently recom-mended multidrug therapy (MDT) regimensfor Zaire do not appear in the treatmentsection, which does describe several MDTregimens, including a modified WHO-rec-ommended regimen. Although not specifi-cally written for Zaire, the book will find itsgreatest readership there, and any new edi-tion should describe regimens currently inuse in that country.

In summary, this is a book that shouldbe widely distributed among field workersin French-speaking Africa. Hopefully, a sec-ond revised and corrected edition will ap-pear within the next 2 or 3 years.— L. 0.Lanoic

Hastings, R. C., ed. Leprosy. (Medicine inthe Tropics Series.) New York: ChurchillLivingstone, Inc., 1986, 319 pp. + index,hard cover, US$62.

This textbook is intended as a compre-hensive summary of the vast amount ofinformation on leprosy published since the1964 edition of Leprosy in Theory andPractice, edited by Cochrane and Davies. Itis a courageous and successful undertaking.

The contributors are well experienced intheir respective fields and possess a fluencyof thought and expression that is apparentthroughout the 14 chapters.

In the lead chapter, the late Stanley G.Browne outlines the history of leprosy,

starting with a description of the earliestobjective evidence of the disease in the skullbones of four Egyptians buried in the oasisof Dakhleh in the 2nd century B.C. to itsintroduction into the New World by theSpanish and Portuguese conquistadores andAfrican slaves. Browne's extensive experi-ence in leprosy is evident as he describesthe evolution of the treatment of the diseasewith the personal insight of a clinician whoexperienced the transition from an era whenno effective treatment was available to onein which the clinician could select fromamong several drugs to effectively controlthe disease in patients under his care.

Nordeen provides an excellent overviewof the epidemiology of leprosy, describingits distribution according to geography, age,sex, ethnic factors, time, and socioeconomicfactors. Recent information on reservoirs ofthe infection, portal of entry and exit ofAly-cobacterium leprae, methods of transmis-sion, and possible routes of infection arediscussed.

Rees' chapter on microbiology includesrecent advances in biochemical studies ofAl. leprae, and details the procedures need-ed to assess the bacteriological status of pa-tients.

Harboe's mastery of the field is evidentin his chapter on the immunology of lep-rosy. He starts by constructing an immu-nologic profile of Al. leprae that includes adescription of monoclonal antibodies againstAl. /eprae-specific antigens. This is followedby a shift to an immunologic portrait of theinfection itself that details the immunologicaspects of subclinical infection, indetermi-nate leprosy and, finally, persisting deter-minate disease. A summary is presented ofthe most significant studies on the possiblerole of T4 helper cells and T8 suppressorcells, with emphasis on the dinrences indistribution of T4 and 1'8 cells in the gran-ulomas of tuberculoid versus lepromatousleprosy. Harboe describes the immunode-ficiency of lepromatous leprosy and dis-cusses the importance of interleukin-2 inrestoring the immune response in patientswith lepromatous disease. He also presentsa well-organized description of the signifi-cance of antibodies in leprosy (an area whichreceives little attention in many discussionsof the immunology of leprosy), and con-cludes with a commentary on the potential

666^ International Journal of Leprosy^ 1986

value of vaccines used either prophylacti-cally or therapeutically. Harboe's contri-bution to the text is invaluable.

Dharmendra's chapter on classificationshould help clinicians to resolve such dif-ferences of opinion that are due to termi-nology and not conflicting clinical findings.

The chapter on clinical leprosy by Pfaltz-graff and Bryceson, and the chapter describ-ing the pathology of leprosy by Ridley andJob, are comprehensive and well illustrated.Seventy-three photographs depicting clini-cal aspects and 34 photographs illustratinghistopathologic features provide the readerwith an excellent opportunity to correlatethe clinical and histopathologic findings inpatients suffering from the different types ofthe disease and its complications.

Leiker's chapter on differential diagnosisprovides numerous illustrations of greatvalue to the clinician who must be able torecognize those diseases that may be con-fused with leprosy. The chapter on treat-ment by Jacobson will also be helpful to theclinician in designing appropriate treatmentregimens.

Margaret Brand's and T. ffytche's reviewof eye complications of leprosy, and Bar-ton's chapter describing the ear, nose, andthroat involvement in leprosy patients,demonstrate that leprosy can involve morethan skin and peripheral nerves, and em-phasize the need for careful evaluati6n andtreatment when these vital tissues are in-volved.

The chapter on experimental leprosy bythe late C. C. Shepard contains a compre-hensive and detailed description of the an-imal models used in leprosy. The advan-tages and disadvantages of each model aredescribed. This chapter provides an excel-lent review of all the studies done using themouse foot pad model, and because Shep-ard pioneered the use of the mouse foot padin leprosy, the interpretation of the resultsin mice is keen and insightful. It should benoted that in this chapter the possibility ismentioned that M. leprae may be reclassi-fied from a Biosafety Level 2 category, inwhich it is considered less of a biohazardthan Al. tuberculosis and other pathogenicmycobacteria, to a Biosafety Level 3 cate-gory, which requires special and unusualprecautions when handling the agent. Since

then, however, in the revised 1984 editionof the CDC/NIH publication entitled Bio-safety in Microbiological and BioniedicalLaboratories, Al. leprae retains its Level 2classification and is considered of onlymoderate potential hazard to personnelhandling the organism.

The chapter on control programs by Le-chat, and the final chapter on rehabilitationby Paul Brand and Ernest Fritschi, are in-formative and provide the practical infor-mation so important in dealing with theseaspects of leprosy.

Dr. Browne concludes his chapter on thehistory of leprosy with the statement: "Thelast page of the 'strange, eventful history' ofleprosy has not yet been written. The re-doubtable Mycobacterium leprae is still ca-pable of surprising and challenging the peo-ples of the world." This textbook willprovide clinicians and researchers in lep-rosy with a greater ability to meet these sur-prises and challenges.—Gerald P. Walsh

Ramalingaswami, V. Annual Report of theDirector-General 1984-85, Indian Coun-cil of Medical Research. Satyavati, G. V.,ed. New Delhi: ICMR Offset Press, 1986.Softbound, 113 pp.

[The following is that portion of the re-port dealing with leprosy.]

Research on various aspects of leprosywas continued at the Council's Central JAL-MA Institute for Leprosy (CJIL) at Agra andalso at other institutes/centers at Chingle-put, Madras, etc.

ChemotherapyChemotherapeutic trials using the newer

anti-leprosy drugs in different combinationswith DDS were continued at the CJIL, Agra.A combination of rifampin, prothionamide,isoniazid and DDS has been found to behighly effective in lepromatous leprosy. Tostudy the effect of prothionamide in reduc-ing infectivity, a study was undertaken atthe CJIL, in two groups of patients on twodifferent doses viz. 250 mg daily and 500mg daily. Monotherapy with the drug wasgiven for two months. At the end of eightweeks, no viable organisms were found ineither of the groups indicating that pro-thionamide is a very effective drug. It was

54, 4^ Book Reviews^ 667

also observed that lower doses producedlesser side effects.

Immunological StudiesWhile studying the antigens of mycobac-

teria, a special silver staining technique toidentify the antigens of Mycobacterium lep-rae, Dharmendra lepromin, Al. vaccae andM. tuberculosis (H37Ra) was attempted.This comparative study showed commonas well as distinct antigenic bands in thesemycobacterial species. Dharmendra lepro-min was evaluated in four different centresand all the centres have provided compa-rable results. In an effort to determine therole of antibody in activation of the alter-native pathway of complement, it was foundthat anti-Al. vaccae serum was able to sig-nificantly increase the activation of com-plement. A similar study is in progress withM. leprae.

Efforts have been made to detect immu-noglobulins and Al. leprae antigen in urineof patients of leprosy. IgG, IgA and IgMwere detected in the urine of patients of lep-rosy, whereas all the healthy volunteers werenegative except one in whom the urine sam-ple was positive for IgG. M. leprae antigenhas also been detected in some of the sam-ples.

Diagnostic StudiesA radioimmunoassay based on quasi-

specific anti-M. leprae monoclonal anti-body MLO4 has been developed by the CJIL,Agra. This is likely to provide a highly spe-cific and sensitive diagnostic test for lep-rosy. Its efficacy in the identification of lep-rosy patients and their household contactsis being assessed.

Studies employing FLA-ABS and lepro-min tests have been extended to cover near-ly 200 household contacts of patients atLeprosy Clinic at CJIL, Agra, and LeprosyControl Unit at Deeg (Bharatpur District,Rajasthan). FLA-ABS positivity was higherin contacts of multibacillary patients, ascompared to contacts of paucibacillary pa-tients. There was no correlation in the reac-tivity of either lepromin or FLA-ABS testswith sex of the contacts. In the contacts ofmultibacillary forms, the lepromin positiv-ity was low in 0-5 and 6-10 years age groupswhereas FLA-ABS positivity was high. The

FLA-ABS is a better parameter than theskin test for the detection of subclinical in-fection in younger age groups. It may alsohelp to understand the temporal relation-ship between humoral and cell mediatedimmune responses.

Investigations aimed at detecting sub-clinical infection and pre-clinical state werecarried out using several methods such as(i) Nasal mucosal biopsies; (ii) lepromin skintest; (iii) FLA-ABS test; (iv) bacillaemia bythe haemolysis method; (v) serological as-say for antibody activity by serum inhibi-tion of binding of II" labelled MLO 4 mono-clonal antibody; and (vi) quantitation ofcirculating mycobacterial immune com-plexes by using a standardized ELISA tech-nique. Of these methods FLA-ABS wasfound to be the single best test for detectingsubclinial infection, being positive in 79.12per cent patients.

The Regional Medical Research Centre,Bhubaneswar, has initiated studies on an-tigenic analysis of mycobacteria. The M.leprae specific phenolic glycolipid-I antigenhas been isolated from tissues obtained fromlepromatous leprosy patients and specificantisera are being made. These antisera willbe used to develop a method for early de-tection of infection with Al. leprae. Analysisof specific restriction fragments of myco-bacterial DNA has been started with a viewto developing a system for identification ofM. leprae on the basis of a unique sequenceof DNA.

Evaluation of VaccinesA few candidate vaccines against leprosy

were evaluated by using the mouse foot-padtechnique. Animals were vaccinated intra-dermally with autoclaved intact M. leprae,M. w., ICRC bacillus and M. vaccae indi-vidually as well as in combination with liveBCG. Mice immunized with nit% gave thehighest induration, whereas induration wasslightly less with M. leprae and ICRC ba-cillus. Addition of BCG to the antigens didnot enhance the DTH reaction. At 48 hours,the reaction was greater with BCG+ICRCand BCG +M. leprae followed by BCG+M.vaccae. Reaction with BCG +M. w. was poor.In mice challenged with live M. leprae infoot-pads, Af.w. gave the best protection bycomplete suppression of the infection, ICRC

668^ International Journal of Leprosy^ 1986

and Al. leprae being next in order. Al. vaccaewas found to be non-protective against Al.leprae infection.

Under the Indo-US collaborative Pro-gramme, studies have been undertaken atBombay and New Delhi on various aspectsof leprosy like characterization and biolog-ical significance of specific phenolic glyco-lipids in infected human tissues, develop-ment of M. leprac specific human T cellclones, macrophage metabolism and func-tions, and on the role of dendritic cells inthe antigen induced in vitro lymphoprolif-erative responses.

Drug ResistanceA random study conducted to screen re-

sistant strains of AI. leprae in lepromatouspatients from eight Northern states of Indiarevealed 69 clinically suspected patients ofwhom 33 harboured Al. leprae with variousdegrees of dapsone resistance. Most of thesepatients were from Uttar Pradesh and Ma-dhya Pradesh.

An epidemiological study conducted inDharmapuri and Pallipatti areas of TamilNadu for a period of 5 years to assess theprevalence of drug resistance revealed 266bacteriologically positive patients out of6664 leprosy patients. Among these, 25 pa-tients were suspected clinically to be dap-sone-resistant. The prevalence rate of drugresistance was found to be 1.1 per cent inthese two areas using the mouse foot-padtechnique.

Surgical RehabilitationCollapse of nasal architecture persists in

patients of multibacillary leprosy, particu-larly if they remain untreated for a long time.One stage nasal reconstruction using bonegrafts (modified Brand's procedure) is beingdone for moderately deformed patients atthe CJIL, Agra. Ten patients operated dur-ing the year under report were followed upfor survival of graft, its absorption at therecipient site and donor site complications.There were no local complications in thedonor foot from where the metatarsal bonehad been removed and used as a graft. Thegrafts retained well without any local sepsisor extrusion. Clinically, there was no sig-nificant absorption of the grafts.

A long term follow up study of corrected

claw hands is in progress at the CJIL, Agra.Eighty five claw hands (of 78 patients) werestudied during the year under report fromdifferent occupational groups. Post-opera-tive evaluation was done for stiffness ofhand, closure pattern of fingers, fist closure,grip power, post-operative deformities, sub-sequent injuries and infections. Only sevenoperated hands out of 85 had evidence ofinjury or infection. Sublimis minus defor-mity was seen in 14 patients out of 39 butthis was not disabling. Stiffness graduallydisappeared with time and the grip im-proved.

Sociological and PsychiatricMorbidity Studies

A sociological study of two colonies ofpatients comprising (i) self-rehabilitated pa-tients near CJIL, Agra and (ii) beggars inBijnor district, Uttar Pradesh, showed thatper capita income in the self-rehabilitatedpatients is higher, social acceptance is great-er and treatment status was better than inthe beggar group.

Psychiatric morbidity in 93 patients at-tending the clinic at JALMA revealeddepression and anxiety, which was signifi-cantly enhanced in patients who had reac-tional episodes.

Transmission StudiesInvestigations on the possible role of bit-

ing arthropods as vectors in transmission ofAl. leprae from man to man were carriedout at the CJIL, Agra. The phlebotominesandflies and leprosy co-exist in tropical andsubtropical countries where the climate isdry and humid. Screening of sandflies caughtfrom houses in the vicinity of the leprosyhospital as well as from houses far from thehospital revealed that 19 sandflies out of 50caught near the hospital harboured acid fastbacilli. Those caught from houses away fromthe hospital did not show any AFB. Inves-tigations are in progress to isolate and iden-tify the AFB obtained from the gut contentsof sandflies.

Morphological StudiesLeprosy is a polymorphic granulomatous

disease with a spectrum of lesions rangingfrom the paucibacillary epithelioid cellgranulomas surrounded by abundant lym-

54, 4^ Book Reviews^ 669

phocytes in the tuberculoid form of leprosyto lymphopenic lesions with bacilli ladenfoamy macrophages in lepromatous lep-rosy. Studies were carried out to character-ize the cells in the lesions which may leadto a better understanding of the mechanismof granuloma formation in leprosy.

Single cell suspensions from the granu-loma of leprosy patients using collagenasewere prepared to enable an in vitro study ofthe properties of infiltrating cells. The gran-ulomas were found to contain lymphocytesand 'large cells' (epithelioid cells and mac-rophages). The number of lymphocytes wassignificantly higher in the suspension of tu-berculoid granuloma in comparison to thesuspension from lepromatous granuloma. Ahigh percentage of lymphocytes from tu-berculoid granuloma formed rosettes withsheep erythrocytes and also showed thepresence of esterase as dots in the cyto-plasm. However, the lymphocytes did notform any rosettes with sheep erythrocytessensitized with antibodies and complement(EAC). Most of the large cells from both thegranulomas were esterase positive, exhib-ited peroxidase activity and did not carryreceptors for the C3 component of comple-ment. A high percentage of large cells in thetuberculoid granuloma was non-adherent toplastic surface as compared to lepromatousgranuloma which contained a high propor-tion of adherent large cells. These obser-vations indicated that (i) the lymphocytesderived from a tuberculoid granuloma ap-pear to be T-lymphocytes, and (ii) the largecells in both the granulomas appear to be-long to cells of the mononuclear phagocyteseries. Studies are in progress to characterizethese cells using monoclonal antibodies andother cell biological techniques.

Pathological changes that occur in skinand nerves of leprosy patients during thecourse of infection were observed in ultra-thin sections. Sections of tissues from bor-derline tuberculoid leprosy patients showedvascular changes of the mitochondria in thecytoplasm of the giant cells. Epithelioid cellsshowed clusters of M. leprae as well as mye-linated droplets in their cytoplasm. Border-line lepromatous lesions showed myelinat-ed nerve fibres and intact bacilli in maturefoamy cells. Sections of lepromatous nerveshowed a large number of bacilli inside

Schwann cells and degeneration of the nu-cleus of the cell.

Microbiological StudiesIsolation and characterization of myco-

bacterial mycolates at CJIL, Agra, showedthat mycobacterial species can be classifiedinto five groups on the basis of unidimen-sional thin layer chromatography. Analysisof mycolates extracted from leprosy infect-ed tissues showed presence of alpha and ketomycolates in AI. leprae. This pattern is notshown by any other related taxon and there-fore is of paramount taxonomical impor-tance.

A preliminary investigation revealed thatesterases are present as isoenzymes in var-ious species of mycobacteria. Their role inclassification and identification is beingstudied.

The difference in morphological structureof bacilli is an important factor to know theefficacy of antileprosy drugs. Structuralchanges were observed in Al. leprae in lep-rosy tissues before and during adequatetreatment.

Ridley, Dennis S. Skin Biopsy in Leprosy.2nd ed. Basel: CIBA-GEIGY Limited,1985. Softbound, 63 pp., includes indexand color plates. Available free of chargefrom CIBA-GEIGY.

The second edition of the book, Skin Bi-opsy in Leprosy, authored by Dr. Dennis S.Ridley, has incorporated most of the ad-vances in the pathological study of leprosysince the first edition was published nineyears ago. The author's work on the clas-sification of the disease is so well knownthat perhaps he is the most frequently quot-ed person in leprosy literature.

The book, as expected, is properly orga-nized, beautifully illustrated and extremelywell presented. Several new sections havebeen added which increases the usefulnessof the book. The section on diagnosis anddifferential diagnosis will be very helpful,particularly to those pathologists who donot routinely see biopsies from leprosy pa-tients. By and large the book sticks to theinternationally recognized Ridley-Joplingsix-group classification of the disease.

This book will no doubt continue to serve

670^ International Journal of Leprosy^ 1986

a useful purpose and will be referred to byevery pathologist involved in leprosy work.

May I congratulate the author and com-pliment CIBA-GEIGY for making this ex-cellent reference book available free ofcharge to leprologists and to pathologistsinterested in leprosy.—C. K. Job

Thangaraj, R. H. and Yawalkar, S. J. Lep-rosy for Medical Practitioners and Para-medical Workers. Basel: CIBA-GEIGYLimited, 1986. Softbound, 92 pp.

With this booklet, the authors intend toinform nonspecialists, physicians, and para-medical workers about the major aspects ofleprosy. As a publication of CIBA-GEIGY,the booklet represents another indication ofthe company's long-standing commitmentin the fight against the disease.

The booklet is superbly produced and isobviously the product of authors with acomprehensive understanding of leprosy. Aspointed out by Dr. S. K. Noordeen, ChiefMedical Officer, Leprosy, of the WorldHealth Organization in an introduction tothe booklet, the challenge of leprosy can onlybe met by comprehensive control effortswith participation at all levels including

general medical practitioners. The bookletis intended as a guide for all individualsengaged in leprosy work. It is remarkablycomplete in covering the essentials of thedisease and its management. Fourteenchapters outline the major points in the his-tory of the disease, its epidemiology, bac-teriology, clinical features, differential di-agnosis, essentials of diagnosis andtreatment, reactions and their management,the management of deformities, the pre-vention and control of the disease, and fi-nally a chapter emphasizing the importanceof rehabilitation programs as an integral partof every leprosy control program. The num-ber of references for the entire booklet islimited to 100, and the list is followed byrecommendations for further reading and alisting of historical milestones in the fieldof leprosy since 1873.

The booklet is a masterful condensationof the essence of leprosy, and Dr. Thangarajand Prof. Yawalkar are to be congratulatedtogether with CIBA-GEIGY Limited inhaving produced an extremely attractive aswell as useful guide for nonspecialists calledupon to care for leprosy patients.— RCH