INTERNATIONAL JOURNAL OF LEPROSY^ Volume 61, Number IPrinted in the U.S.,!.

Clinical Features and Outcome of Reversal (Type 1)Reactions in Hyderabad, India'

Diana N. J. Lockwood, Solomon Vinayakumar,John N. A. Stanley, Keith P. W. J. McAdam, and

M. Joseph Colston 2

Reversal reactions (type 1 reactions),which are an important complication of lep-rosy, are episodes of acute inflammation af-fecting skin and nerves occurring when apatient develops increased cell-mediatedimmunity toward Mycobacterium leproc(' ') and moves toward the tuberculoid endof the leprosy spectrum. Ridley and Radia( 13 ) have described the histological featuresof reversal reactions which include edema,lymphocytic infiltration and giant cell for-mation. The outcome of this cellular acti-vation is the elimination of leprosy bacilliwith a fall in the bacterial index (BI) (").Since this acute immune response is di-rected at M. leprae antigens, the inflam-matory response is seen at the sites of lo-calization of M. leprae antigens, skin andperipheral nerve, and is manifest clinicallyas inflammatory skin lesions and acute neu-ritis. It is this neuritic component of rever-sal reaction pathology which is particularlyimportant because unless neuritis ispromptly diagnosed and treated, rapid andsevere nerve damage may ensue. Despitethe practical importance of reversal reac-tions there have been few studies of theirepidemiology or natural history. We havefocused solely on reversal reactions, and arenot considering here the other major reac-tional state in leprosy, erythema nodosumleprosum (ENL; type 2 reactions).

The data presented here were collectedduring a retrospective study of case notes at

' Received for publication on 7 April 1992; acceptedfor publication in revised form on 19 November 1992.

1 D. N. J. Lockwood, M.R.C.P.; K. P. W. J. Mc-Adam, F.R.C.P., Department of Clinical Sciences,London School of Hygiene and Tropical Medicine,Keppel Street, London WC I E 7HT, U.K. S. Vinayaku-mar, M.B.B.S.; J. N. A. Stanley, M.B.B.S., Ph.D.,Dhoolpet Leprosy Research Center, Karwan, Hyder-abad 500006, India. M. J. Colston, Ph.D., NationalInstitute for Medical Research, The Ridgeway, MillHill, London NW7 IAA, U.K.

Dhoolpet Leprosy Research Centre, Hyder-abad, India. The study was designed to doc-ument a) the frequency of reactions; b) thetiming of reactions, particularly in relationto the onset of leprosy symptoms and treat-ment; c) the symptoms and signs of reac-tion, particularly the signs of neurologicalinvolvement; d) the response to treatmentand e) the frequency of late reactions.

METIIODSThe Dhoolpet clinic is situated on the edge

of Hyderabad old city. It does not have aleprosy control program so most patientsare self-referred, with a few being referredfrom local practitioners. The clinic is fund-ed as a research center by the British Med-ical Research Council, and has developed astrong interest in nerve damage under thedirection of Dr. J. M. H. Pearson (who wasthe clinician in charge in 1985). All notesfor patients registering as new cases with theclinic from 1 January until 31 December1985 were reviewed in March 1991 by oneperson (DNJL). These dates were chosen toallow a lengthy follow up for the detectionof late reactions. Patients who did not haveleprosy or did not attend again were ex-cluded from the analysis. All patients hadbeen seen by either one of the two cliniciansrunning the clinic. A reversal reaction wasdeemed to have occurred if any of the fol-lowing criteria were met: a) there was newerythema of existing skin lesions withoutevidence of downgrading, b) there were newerythematous skin lesions without the fea-tures of ENL, c) new acute neuritis, or d)the histopathological report was of a rever-sal reaction. Data were collected on age, sex,time at which symptoms of leprosy werefirst noted, commencement of treatment,and appearance of reactional lesions. Par-ticular attention was paid to the symptomsand signs of reversal reactions, the descrip-

8

61, 1^ Lockwood, et al.: Reversal Reactions^ 9

tion of skin lesions and neuritis. Recordswere specifically examined for data on theulnar, median, radial, radial cutaneous, lat-eral popliteal (common peroneal), posteriortibial and sural nerves. For those nerves,the following symptoms and signs were spe-cifically recorded: nerve tenderness; motorsymptoms (symptomatic weakness); signsof paresis (a score of less than 5/5 using theMRC testing scale); sensory symptoms (par-esthesia, anesthesia) and sensory signs (di-minished sensation to pin prick, light touchor temperature). Treatment details for thereversal reactions were noted together withthe time it took for improvement to occur.Any further reactional episodes were noted.

RESULTSA total of 810 new cases were registered

at the clinic between 1 January and 31 De-cember 1985, of these cases 144 were notleprosy and 167 were seen only once andwere not included in the study. The noteson five patients were unavailable. The studypopulation of 494 was clinically classifiedas tuberculoid (TT) 77 (15.6%); borderlinetuberculoid (BT) 218 (44.1°/0); midborder-line (BB) 3 (0.6%); borderline lepromatous(BL) 67 (13.5%); lepromatous (LL) 123(24.8%) and 6 "others" (5 indeterminate, 1polyneuritic case).

A total of 45 patients met our definitionof reversal reaction during the 6-year studyperiod; 1 patient was subsequently excludedbecause his histology report showed evi-dence of relapse, leaving a reversal reactiongroup of 44 patients-52.3% of reversal re-actions were in males, 47.7% in females.The age range of the patients at the time ofreaction varied from 12-89 years (mean 35years). Diagnostic skin biopsies were donein 27 patients. The clinical and histologicalclassifications were concordant in only 15cases, of the remaining 12 patients 9 werecloser to the tuberculoid end of the spec-trum and 2 were more lepromatous thananticipated on clinical examination. Theselatter two patients were clinically classifiedas BL but on histology the classification wasof subpolar lepromatous (1_,L) in reaction;they also both responded to steroids whichhelps confirm their reactional state. For ouranalysis a patient's classification is his/herhistological one when histology has been

TABLE 1. Classification of total patientcohort and reactional patients.

ReactionalNo. reac- patients in

tional each classi-patients^fication

group

TT 77 3 3.8BT 218 25 11.41313 3 3 100BL 67 10 14.8LL 123 3 2.4Indeterminate 5 0 0Polyncuritic 1 0 0Total 494 44

done, otherwise it is his/her clinical one.Table I gives the classification of the 44patients studied. Reversal reactions are mostlikely to occur in patients from the border-line groups (BT, BB and BL) with 86.3% ofour patients being in these borderline groups.

Data on patient BIs were available for 12patients before, during and after reaction;on 38 patients during reaction and on 18during and after reaction. All BIs fell or re-mained at 0 before, during and after reac-tion with the exception of one patient whoseBI fell from 3.7 at presentation to 0 duringreaction and then rose a year later to 2.3when he relapsed. His reversal reaction hadbeen confirmed histologically.

In 1985 the World Health Organization(WHO) multidrug therapy (MDT) had notbeen introduced for all patients in Hyder-abad, and so 37% of the patients had beentreated with dapsone (DDS) alone, 56.5%with DDS and rifampin and 6.5% with DDS,rifampin and clofazimine.

Clinical features of reversal reactions. Ofthe 44 patients who had a reversal reaction,19 (43.1%) had skin lesions alone, 10 (22.7%)had both skin lesions and neuritis, and 14(31.8%) had only neuritis (Fig. 1). One pa-tient was found to have histological evi-dence of reaction on a skin biopsy from anonreactional-looking lesion; 26 patientshad erythematous skin lesions and in only9 cases was edema present also. No ulcer-ation of skin lesions was noted. New skinlesions were reported in 5 patients (2 BT, 3BL).

There was evidence of neuritis in 24(54.5%) patients. (Table 2 shows for each

No.

Classification^studypopu-lation

Both skin lesionsand neuritis

Total group of44 patients in reaction

1 patientNo skin lesionsNo neuritis

Ulnar Posttibial

Facial

Lateralpopliteal(commonperoneal)

Median

10^ International Journal of Leprosy^ 1993

FIG. 1. Distribution of skin lesions and neuritis in44 Indian reactional patients.

peripheral nerve the percentages of patientnerves that were found to have evidence ofneuritis.) There was no evidence for later-alization of the neuritis. The ulnar nerve isthe most commonly affected nerve by anyparameter of neuritis, with nerve tendernessbeing found in 25% and motor signs in 33.3%of the nerves examined. Nerve tendernesswas rarely elicited in the lateral popliteal(common peroneal) and posterior tibialnerves, although evidence of motor dys-function was found in 14.5% of lateral pop-liteal nerves. No evidence of radial nerveinvolvement was recorded, although fourradial cutaneous nerves were reported to betender. Nine patients had neuritis in onenerve only, five patients were affected in twonerves and 10 patients had multiple nerveinvolvement. A score was constructed todetermine the severity of neuritis: for eachnerve 1 point was allocated for each possiblesign of neuritis (tenderness, sensory symp-toms, sensory signs, motor symptoms, mo-tor signs). For 10 nerves the maximum pos-sible score was 50. (Table 3 gives thedistribution of scores.) Patients who hadneuritis usually had more than one sign of

FIG. 2. Time intervals from initial symptoms of

leprosy to development of reactional skin lesions andneuritis. Skin = 0; nerve = O. Median symptom-re-

action time: skin = 13.0 mos. 37.8 mos; nerve =27.5 mos.^33.1 mos.

neuritis. Paucibacillary and multibacillarypatients did not differ in their clinical pre-sentation of reactions with respect to thepresence of skin lesions or the numbers andtypes of nerves involved.

Figure 2 shows the numbers of patientsdeveloping symptoms of skin and nerve re-actions during defined time intervals fromtheir first symptoms of leprosy. The periodof 12-24 months after first symptoms is thepeak time for the development of reactionalsymptoms, although reactional symptomsoccurred as long as 12 years after the initialsymptoms of leprosy. Skin reactional symp-toms developed earlier than neurologicalsymptoms, with a median first symptom-to-reaction time for skin lesions of 13.0months (S.D. 37.8 months) and 27.5 months

TABLE 2. Clinical features of neuritis and percentages of nerves found to have signs ofneuritis.

Nerve tenderness 25.0 12.5 2.0 4.0 0Sensory symptoms 22.9 16.6 8.3 8.3 0Sensory signs 29.1 20.8 6.2 8.3 0Motor symptoms 33.3 12.5 10.4 4.1 8.3Motor signs 33.3 14.5 14.5 4.1 12.5

61, 1^Lockwood, et al.: Reversal Reactions^ 11

(S.D. 33.1 months) for neuritis. There werea substantial number of patients in whomthe diagnosis of leprosy was only consideredwhen they developed a reaction.

Reactional symptoms developed in 45.4%of our patients before they sought treatmentfor leprosy, 38.6% were on treatment at thetime of reaction, and 9% developed reactionafter treatment (treatment details were in-complete for three patients). Only one pa-tient admitted to previous irregular treat-ment. Of the 17 (1 TT, 10 BT, 1 BB, 4 BL,1 LL) patients who were on treatment at thetime of reaction, 6 were receiving DDSmonotherapy, 2 of whom were irregular intaking their medication. Ten patients wereon DDS and rifampin; 1 was irregular. Onepatient was on multibacillary MDT.

We have analyzed the temporal relation-ship between starting treatment and a re-action separately for skin lesions and neu-ritis (Fig. 3). The median treatment-to-skin-lesion interval is 1.0 month (S.D. 18.4months); for neuritis, 3.0 months (S.D. 17.8months). Of patients developing skin reac-tions 25% had done so more than 1 monthbefore seeking treatment, while 32% soughttreatment at the time of new, acute symp-toms. Of the 12 patients developing a skinreaction after starting treatment six did sowithin a month of starting treatment. A fur-ther five patients developed reactions morethan 6 months after starting treatment, withone patient having a skin reaction 74 monthsafter starting treatment.

The timing of neurological reactions inrelation to treatment is shown in Figure 2;21.1% of patients reported neurological signsin the 6 months before treatment was start-ed, a further 21.1% at the start of treatment,and 36.3% of patients developing neuritis

Month., • start al treatment to reaction

FIG. 3. Time intervals from start of treatment todevelopment of reactional skin lesions and neuritis.Skin = ID; nerve = EL Median treatment-reaction time:skin = I mo. ± 18.4 mos; nerve = 3 mos. ± 17.8 mos;0 = at presentation.

on treatment did so in the first 7 months.The remaining patients developed neuro-logical signs at a steady rate up to 50 monthsafter the start of treatment. We found nodifference in the timing of either skin orneurological reactions from the start oftreatment between paucibacillary and mul-tibacillary patients.

Seven patients (5 BT, 2 BL) developedreactions more than 24 months after start-ing treatment. Four patients had signs inboth skin and nerve, three in skin alone.The BT patients had received either DDSmonotherapy (N = 2, one irregularly) orDDS and rifampin. The BL patients hadtaken DDS and rifampin, one irregularly.

Treatment. Prednisolone was used totreat 63% of the patients, and all patientswith any evidence of neuritis received ste-roids. The dosages used ranged from 10-30mg daily (mean 15 mg daily). The exam-ining clinician's notes were used to deter-mine whether a lesion had improved or re-solved. Skin lesions were more likely thanneuritis to improve on treatment with im-provement being noted in 93.1% of skinlesions and only 50% of neuritic episodes.The response of skin lesions also startedquickly, with 38.1% improving at 1 monthand 81.0% improving by 6 months. Corn-

12^ International Journal of Leprosy^ 1993

plete resolution of skin lesions occurred inonly 52.9% of the patients and had occurredwithin 6 months for 35.7% of this group;for 85.7%, by 12 months.

Neurological improvement was deemedwhen there was either a recorded subjectiveimprovement of symptoms or a discernableimprovement on motor or sensory testing;50% (N = 12) of the patients with neuritishad some neurological improvement, 5 pa-tients were lost to follow up, and 7 did notimprove. Comparing those who improvedwith those who did not showed no differ-ences in the type of disease, pattern of nerveinvolvement (single nerves versus multiplenerves), or dose of steroids used. The neu-ritis severity score was higher for improversthan for nonimprovers (7.25 vs 5.6). Re-versal reactions had been confirmed histo-logically for three of the nonimprovers, andthere was no deterioration in the BIs or clin-ical evidence of relapse in the other four.Thus, failure to improve was not due toundiagnosed relapsing disease. Neurologi-cal improvement occurred more slowly thanskin improvement, with a mean time to im-provement of 8.5 months. Complete reso-lution of neurological signs was rare, oc-curring in only two patients.

Recurrent reactions. Fourteen patients(6 paucibacillary, 8 multibacillary) had afurther reaction, either worsening or new

skin lesions, or worsening or new neuritis.Skin biopsies were done on six patients, andall biopsies confirmed the presence of eithera reversal reaction or active disease; no ev-idence of relapsing disease was found. Sevenpatients had just one recurrence, and of theremaining 7 patients, 1 patient had two re-currences, 2 had three recurrences, 3 hadfour recurrences, and 1 had five recurrences.Recurrences occurred up to 40 months afterthe initial diagnosis of reversal reaction withthe peak incidence during the first 6 monthsafter the first reactional episode. Recur-rences seemed equally likely to affect skinor nerve, with 50% of the patients havingepisodes of neuritis. There was some re-sponse to further courses of steroids; of 8patients treated with steroids, 4 improved,2 deteriorated and 2 remained static.

DISCUSSIONAlthough reversal reactions are a well-

recognized complication of leprosy, thereare few published reports of their frequencyand natural history ('"' ' 4 ). Our data shouldbe interpreted with some caution since thestudy is retrospective and derived from aself-referred population rather than a pop-ulation in a leprosy control area. This mighttend to produce high figures for the inci-dence of reversal reactions, since patientsin reaction may be prepared to travel to aclinic known to have an interest in nervedamage. The retrospective nature of thestudy also precluded us from studying pos-sible etiological factors that may precipitatereactions.

Our data confirm previous observations12 ) that borderline patients are most likely

to develop reversal reactions, with 11.4%and 14.8% of BT and BL patients devel-oping reactions compared with only 3.8%and 2.4% of TT and LL patients, respec-tively. However, it is important to note thatTT and LL patients may develop reactions;the three LL patients presenting with reac-tional lesions were all histologically sub-polar lepromatous (LL,).

Our findings emphasize the immunolog-ical instability of borderline patients, manyof whom had developed reactions sponta-neously. This instability is reflected in thecomparison of clinical and histological find-ings where we found that 33% of the patientshad a skin biopsy more tuberculoid than the

61, 1^ Lockwood, et al.: Reversal Reactions^ 13

clinical picture, suggesting that the patientwas upgrading rapidly with the skin signslagging behind the histological picture. It isstriking that although 41.3% of our patientshad presented in reaction yet, on question-ing, they admitted that they had leprosysymptoms for several months. Probablymany patients are prompted to seek treat-ment only when they develop reactional skinlesions, particularly facial lesions or neuri-tis. All patients were asked about previoustreatment, and none of the patients pre-senting with leprosy for the first time andin reaction admitted to having taken priortreatment. In any future study it would beuseful to check that no dapsone (DDS) hadbeen taken recently by screening the urinefor dapsone.

Like Naafs and Wheate ( 10) we feel thatspontaneous reversal reactions are a featureof borderline disease, and are not necessar-ily a result of antileprosy treatment as hasalso been suggested ( 5 ). However, there is aclear association between the initiation oftreatment and the development of reac-tions, with 50% of our patients developingreactional skin lesions within I month ofstarting treatment and a further 25% goinginto reaction within the first 12 months oftreatment. Neurological reactions developmore slowly after starting treatment, with36.3% of neuritic episodes developing with-in 7 months of treatment.

Boerrigter, et al. ( 2 ) found in Malawi thatthe risk of reversal reaction was much high-er in self-reporting patients than in thosepatients found by active case finding. Theself-reporting group probably has more ad-vanced disease and a higher Al. leprae an-tigen load.

It has been shown that reversal reactionsare associated with an increase in lympho-cyte responsiveness to Al. leprae antigens('), and it could be argued that spontaneousreactions result from macrophages destroy-ing bacilli with liberation of Al. leprae an-tigens. When treatment is started many morebacilli are destroyed with the resultant lib-eration of large antigen loads that can thenprovoke a cell-mediated immune (delayed-type hypersensitivity) response. The de-struction of leprosy bacilli will be greatestat the start of treatment, and so this is whenreactions are most likely to occur.

Our data suggest that skin reactions occur

earlier than nerve reactions. This might bebecause people notice skin damage soonerthan nerve damage. Alternatively, it mightbe that Schwann cells are in relatively pro-tected sites with slower killing of bacilli andlater release of antigen, resulting in a lateronset of reactions in nerves.

Although the majority of reactions occuraround the time of initiation of treatment,we found two skin and one nerve reactionsdeveloping more than 4 years after treat-ment was started (one BT, one BL patient).This reinforces the principle that when re-leasing patients from treatment it should beensured that they recognize the symptomsof reactions and understand the need to re-turn for assessment and treatment. Clini-cians should certainly be aware that verylate reactions may occur, and our longesttreatment-reaction interval was 61/2 yrs. Re-versal reactions rarely are reported as beingpotentially recurrent events ( 4 ) yet 33% ofour patients had repeated reactions. Wewould emphasize that reactions frequentlyrecur and patients should be warned of pos-sible recurrences.

It can be difficult to differentiate clinicallybetween relapse and reaction ( 11 ' 6 ). Ideally,a skin biopsy will be available to distinguishbetween the two conditions. In this studywe have adopted a strategy of stringent clin-ical criteria coupled with independent scru-tiny of the case notes and confirmation byappropriate BIs and histology to identifyreactional patients. We do not think thatthose patients who did not respond to ste-roids were in relapse; there was no evidencefrom histology or serial, deteriorating BIsthat they were relapsing. Furthermore, oth-er studies have reported similar improve-ment rates on steroid therapy ( 7 ' 9 ' ' 7 ).

Only 20% of the patients in this study hadboth reactional skin lesions and neuritis.This is an important practical observation,for it means that one must look specificallyfor evidence of neuritis and not rely on thepresence of reactional skin lesions as an in-dicator of potential neuritis. The vulnera-bility of the ulnar nerve to leprous neuritisin reversal reactions is well illustrated byour data. While this might be due to theexposed site of the ulnar nerve, it should beremembered that the ulnar and mediannerves are the easiest nerves to examine.Perhaps a prospective study would show a

14^ International Journal of Leprosy^ 1993

higher incidence of involvement of othernerves ( 15 ).

Steroids have been used with moderatesuccess to treat and ameliorate the nervedamage associated with reversal reactions( 8 ."). While the 1985 regimens used perhapslower and shorter doses of steroids thanwould now be recommended, it is strikingthat while steroids aid resolution of skinlesions they arc less effective in producingimprovement and resolution of neurologi-cal damage. This serves to emphasize theneed for new drugs and approaches to con-trolling reversal reactions.

SUMMARYA retrospective survey of the notes on all

patients attending Dhoolpet Leprosy Re-search Center, India, during 1985 was doneto establish the frequency, timing, and clin-ical features of reversal (type 1) reactions;494 case notes were examined and clinicalevidence of a reversal reaction was foundin 44 cases (10.9%). Reactions were mostcommon in borderline patients, with 11.4%and 14.8% of borderline tuberculoid (BT)and borderline lepromatous (BL) patientsdeveloping reactions, respectively. Presen-tation in reaction was frequent with 47.5%of reactional patients having signs of a re-versal reaction at the time of their first visitto the Dhoolpet clinic; 50% of skin reactionsdeveloping in patients on antileprosy treat-ment occur within the first month of treat-ment. Neurological reactions occur later andover a longer time course. Late reactionsmay occur up to 61/2 years after the start oftreatment. Further reactional episodes oc-curred in 31.8% of the patients, and may berepeated. Steroid treatment produced im-provement of both skin lesions and neuritis,but improvement in clinical signs andsymptoms occurred in only 50% of the neu-ritic episodes.

RESUMENSc hizo un estudio retrospectivo de todos los pa-

cientes atendidos durante 1985 en el Dhoolpet LeprosyResearch Center de Ia India para establecer la frecuen-cia, el tiempo de aparición, y las caracteristicas clinicasde las reacciones reversas del tipo I. Se examinaron494 casos, encontrándose evidencias de reaction re-versa en 44 de los mismos (10.9%). Las reacciunes

fucron mãs comunes en los pacientes con lepra inter-media (1 1.4% en los casos BT y 14.8% en los BL). El47.5% de los pacientes tuvicron signos de reaction re-versa en el tiempo de su primera visita a la clinicaDhoolpet; el 50% de las reacciones en piel ocurrierondurante el primer mes de tratamiento antileproso. Lasreacciones neurológicas ocurrieron después y a lo largode un period() más extenso de tiempo. Las reaccionestardias pueden ocurrir hasty 6.5 aiios despues de co-menzar el tratamiento. El 31.8% de los pacientes pre-sentaron episodios reaccionales adicionales, algunos derepetición. El tratamiento con esteroicles produjo me-joria tanto de las lesioncs en piel como de las neuritis,pero Ia mejoria en los sintomas y signos clinicos soloocurrio en el 50% de los cpisodios neuriticos.

RESUMENous avons realise one etude retrospective des dos-

siers de toes les patients frequentant le "Dhoolpet Lep-rosy Research Center" en Incle en 1985 pour établir lafrequence, lc moment et les caractéristiques dingoesdes reaction reverses (type 1); 494 dossiers ont etc exa-mines et on a trouve one evidence clinque de reactionreverse dans 44 cas (10,9%). Les reactions étaient lesplus frequentes chez les patients borderlines, avec res-pectivement 11,4% et 14,8% des patients borderlinetuberculoides (I3T) et borderline lepromateux (I3L) de-veloppant des reactions. Parmi Its patients qui ontprésenté one reaction, 47,5% avaient des signes de reac-tion reverse au moment de leur première visite ft laclinque de Dhoolpet; 50% des reactions cutanêes sedeveloppant chez les patients en traitement anti-le-preux surviennent au tours du premier mois de trai-tement. Les reactions neurologiques surviennent plustardivement, et s'étalent sur une plus longue période.Des reactions tardives peuvent survenir jusqu'it 61/2 ansaprès le debut du traitement. Des episodes reactionnelsulterieurs sont survenus chez 31,8% des patients, etpeuvent se repéter. Un traitement steroide produit uneamelioration des lesions aussi bien cutanees que ner-veuses, mais ramélioration des signes dimples et dessymptômes est survenue dans seulement 50% des epi-sodes névritiques.

Acknowledgment. DNJL is a Wellcome Trust re-search fellow. Dhoolpet Leprosy Research Center ismanaged by Victoria Hospital, Dichpalli, India, to-gether with the Medical Research Council of GreatBritain.

We would like to thank Dr. J. Keystone and Dr. M.F. R. Waters for helpful criticism of this manuscript.

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