IN ILRNAFIONAL .10FRN SF Or I,LPROSY Volume 47, Number IPrinted in the U.S.A.

Reversal Reaction: The Prevention of Permanent

Nerve Damage

Comparison of Short and Long-Term

Steroid Treatment'

B. Naafs, J. M. H. Pearson and H. W. Wheate 2

Nerve damage leading to permanent dis-ability is one of the major hazards in leprosy.In borderline (BT, BB, BL) leprosy suchdamage usually develops during a "reversal"reaction ( 13 ). When this happens the nervetrunks at specific sites become swollen andtender and show deterioration of function,which is usually rather gradual, takingweeks or even months to become irrevers-ible, but the damage may also occur over-night. The reversal reaction can occur bothbefore and after antileprosy treatment hasbeen initiated ( 12 ).

The mechanism of nerve damage in re-versal reaction is not yet fully understood,but it is thought to he related to immune pro-cesses ) Patients with borderline lep-rosy are able to develop cell-mediated im-munity (CMI) towards M. leprae antigensand it seems likely that an increase in M.leprae antigens, either due to a multiplica-tion of M. leprae or due to a breakdown ofdead and dying bacilli within nerves, cantrigger this response. The nerve is then in-vaded by inflammatory cells and there is anincrease in the permeability of the vascularwall of the intraneural blood vessels, result-ing in interstitial edema with impaired nervefunction and possibly structural nerve dam-age (demyelinization). If the interstitialedema gives rise to raised intraneural pres-sure ( ), the likelihood of permanent dam-age is even greater. Intraneural granuloma

Received for publication 21 August 1978.B. Naafs, M.D.. Clinical Research Physician, All

Africa Leprosy and Rehabilitation Training Center,P.O. Box 165, Addis Ababa, Ethiopia; J. M. II. Pearson,D.M., M.R.C.P., Medical Research Council LeprosyProject, Addis Ababa, Ethiopia; and H.W. Wheate,O.B.E., M.B., B.S., D.T.M.&11., Director of Training,All Africa Leprosy and Rehabilitation Training Center.Dr. Pearson's present address is: National Institute torMedical Research, London NW7 IAA, England.

formation and the organization of intra-neural inflammatory exudate into fibrous tis-sue will cause irreversible damage.

In the management of the leprosy patientwith reversal reaction, it is essential to stopand to reverse the nerve damage. Manytreatment regimes have been tried andclaimed to be more or less successful ( 2-.

14. lb, Is s .) However, prednisolone with its dualaction seems, to date, to be the drug ofchoice ( l". is ). Prednisolone both sup-presses the CMI and decreases the inflam-matory processes, thus decreasing compres-sion and encouraging remyelinization in thenerve. When given for a longer period oftime it may improve nerve recovery by pre-venting scar formation in the nerve.

Testing of voluntary muscle power withthe Voluntary Muscle Test (VMT) has beenused for many years in the Addis Ababa Lep-rosy Hospital to assess the extent of nervedamage in leprosy ( 5 . 9 ) and to monitor theresponse to treatment. However, since 1974prednisolone has been used in higher dosageand for longer periods in the management ofneuritis than formerly. This paper reportsthe results of treatment of reaction with neu-ritis in borderline leprosy, comparing pa-tients treated between 1968 and 1974 withthose treated between 1974 and 1978, usingserial VMT results as the indicator of re-sponse to treatment.

PATIENTS AND METHODS

Patients treated in the period 1974-1978were selected from those attending theAddis Ababa Leprosy Hospital. All wereclinically, and the majority also histopatho-logically, classified as borderline (BT, BB,BL) according to criteria described by Ridleyand Jopling ( 15 ). The patients were consid-ered to be in reaction when there were raisedswollen skin lesions, tender nerves, or when

7

8^ International Journal of Lepros•^ 1979

there was evidence suggesting recent deteri-oration in nerve function.

The patients received prednisolone, 30-40mg daily in a single morning dose for twoweeks; thereafter the dose was slowly re-duced over a period of 4-18 months. Theantileprosy treatment (DDS, 50-100 mgdaily) was continued. Assessments of nervefunction (including sensory testing andmotor nerve conduction velocity measure-ments in addition to VMTs) were performedregularly (at the beginning of the antireac-tion treatment weekly, later monthly, bi-monthly and every six months). When thedose of prednisolone was lowered toorapidly, deterioration in the nerve functionparameters was visible within a few weeksand the prednisolone dose was corrected.Patients were only admitted to the hospitalfor initiation of treatment; they were dis-charged as soon as steroid therapy could belowered below 25 mg prednisolone daily (us-ually after about one to two months in thehospital).

Patients treated in the period between1968 and 1974 who developed reaction orneuritis were usually managed in a "neuritisclinic"; serial VMTs were used to monitorthe response to treatment. Case records ofpatients registered in this clinic were re-viewed and those with borderline leprosyand a reversal reaction who had sufficientnumbers of VMTs performed to enableproper analysis were included in the study.The duration and dosage of antireactiontreatment were recorded, together with anyavailable clinical information.

The VMT was used to compare the effectof treatment in the two groups of patients.As usually performed, this test shows the

TABLE 1. Scoring of VMT-deficit.

V MT-deficit

0 = normal range, normal resistance1= normal range, reduced resistance2 = normal range, no resistance or reduced

range, slight resistance3 = reduced range, no resistance4 = no joint movement but a muscle flicker

5 = muscle paralyzed

power of different muscles on a 0-5 scale (acompletely paralyzed muscle scoring 0; fullpower 5). For this study, however, the scor-ing system was reversed and the "V MT-deficit" scored. Thus: full power = no defi-cit = 0; complete paralysis = total deficit =5. The full system is shown in Table I.

For the ulnar nerve, three muscle groupswere graded: the abductor digiti . tninitni, thefirst dorsal interosseous muscle and the lum-bricales III and IV. The result of the weakerof the last two muscles was added to the re-sult of the abductor digiti tninina and thefirst dorsal interosseous muscle. The maxi-mum VMT-deficit for an ulnar nerve wastherefore 15.

For the median nerve, the abductor pol-/ic is muscle was graded together withthe opponens pollicis and the lumbricales Iand II muscles. The result of the weaker ofthe last two was added to the results of theopponens and abductor pollicis to give theVMT-deficit for the median nerve (maxi-mum 15).

The overall VMT-deficit was obtained byadding the VMT-deficits of both ulnar andmedian nerves together. Complete bilateralulnar and median palsy thus gave the maxi-mum score of 60 points. When the functionimproves, the score is reduced.

RESULTSTable 2 compares the prednisolone dos-

age received by the two groups of patients.Those treated before 1974 received a muchlower dosage after the initial one to twoweeks, and the prednisolone was discontin-ued much sooner, though a few patients hadrepeat courses. A further difference in man-agement was that DDS treatment wasstopped for a period (and almost always re-duced to low dosage thereafter) in the pre-1974 patients.

Table 3 shows that the number of patientswho became worse after one month of treat-ment was much greater in the 1968-1974treated patients. It seems clear that the pro-cess of nerve damage was not arrested bythe short period of high dose prednisolonetreatment used at that time. When a higherdosage was given for a longer period, as in1974-1978, very few patients deterioratedafter treatment was initiated and none afterthe first three months.

Whole trial Discontinued for week 1-2, oftenlow dosage thereafter.

Continued at 50-100 mg daily throughoutthe trial period.

47, 1^Naafs et al: Prevention of Permanent Nerve Damage^ 9

TABLE 2. Clinical management of the trial patients.

l'eriod

Prednisolone dosage per day (mg)

Patients treated 1968-1974

Regime A^Regime B

Patients treated 1974-1978

Week 1Week 2

Week 3Week 4

45-60^15

20^1010^10

5^ 5

30-40

30-40

25-3525-35

Month 2 5^ 5 20 - 30

Follow-up A few patients received 2-3 additionalcourse of regime B, otherwise noprednisolone was administered.

Gradual reduction of dosage: periods offollow-up treatment were:

13T cases 3-8 months13B cases 4 - 12 monthsBL cases 4-18 months

DDS dosage

"FABLE 3. Results of treatment of trial patients.

Time at which maximum nervedamage was observed

25 patients treated1968-1974

23 patients treated1974-1978

Start or after one monthAt three months

At 6-12 months

86

II

194

0

Figure I shows the average VMT-deficitduring and after antireaction treatment. Theperiod 1968-1974 is compared with 1974-1978. In severe reaction (initial VMT-defi-cit > 12) during the period 1968-1974, therewas no improvement of the mean in the firsthalf year after the beginning of antireactiontreatment, though there was a gradual im-provement thereafter, starting at the timewhen the reaction might he expected to sub-side spontaneously. During the 1974-1978period, on the other hand, there was im-provement from the start of ant ireactiontreatment onwards, continuing for over twoyears.

Patients with mild neuritis (initial VMT-deficit < 12) in the period 1968-1974showed no improvement from their treat-ment. Indeed, their mean VMT-deficit after

a three year follow-up period was greaterthan that of patients with severe neuritistreated after 1974. The patients with mildneuritis treated between 1974 and 1978 werecompletely relieved.

DISCUSSIONMany methods have been used to measure

and assess nerve involvement in leprosy.Voluntary Muscle Testing (VMT) has beenused in leprosy for a long time ( 5 ). MotorNerve Conduction Velocity (MCV) hasproved its value (""), and more recentlySensory Testing (ST) has been reintroduced

Using the above-mentioned parameters,Naafs and Van Droogenbroeck ( II) devel-oped an objective method for assessingnerve involvement, the Nerve Deficit Index

0

-o-ems

No

0^9^0-•^-0

6 -A

10^ International Journal of lAprosy^ 1979

REVERSAL REACTION

Severe neuritisx^x _'69-'73, 15 patients

^ .^11 patientsMild neuritis^ o _'69-'73, 10 patients

^ .'74-'78. 12 patients

40 -I

30

UIL

0 20-

xx

10

1 V3^6^9^12^18^24

^36

MONTHSFIG. I. Improvement of borderline patients with neuritis during a three year follow-up period. Short-

term steroid treatment compared with prolonged steroid treatment.

(NDI), which expresses numerically the de-gree of nerve damage. With this method thedose and the length of the antireaction treat-ment for an individual patient can be deter-mined.

Before 1974 the NDI was not used, butcareful VMT assessments were done for pa-tients in reaction. In order to compare the re-sults of treatment regimes before 1974 withthose presently in use, the VMT, which isone of the parameters in the NDI, was used.The VMT had already proved to be a reliableparameter in assessing the degree of nervedamage ( 9 ).

The effectiveness of prednisolone in thetreatment of reversal reaction is well known( 3.6, 17, 19 `.) However, duration and dosage ofthe drug is not yet well defined. With thehelp of the NDI it was possible to adjust theprednisolone treatment for the individual pa-tient in the 1974-1978 period.

It was not possible to reverse the overallVMT-deficit within three months in only 4of the 23 patients treated in this period (Ta-ble 3), though in these patients the reac-tional symptoms (active erythematous skinlesions, rheumatic pain and nerve tender-ness) were settling. In two of these patientsthe nerve damage persisted and did not im-prove at all. It is possible that in these pa-tients and in these nerves the antireactiontreatment was begun too late and it may wellbe that these patients could have benefitedby surgical decompression of the nerves inaddition to steroid therapy. This has beenperformed on similar cases with encouragingresults ( IS ).

It may be concluded from the treatmentresults in the period 1968-1974 that despiteineffective antireaction treatment but withmore or less effective chemotherapy, the re-action settles by itself after six to nine

47, 1^Naa/s et al: Prevention of Permanent Nerve Damage

months. It seems that within this period ef-fective chemotherapy, together with thebody's ability to dispose of M. leprae anti-gens, diminishes the amount of M. lepraeantigens to a level below the "threshold"needed to give rise to a damaging reaction.This is in agreement with earlier findingsthat no reversal reaction was observed in I31and 1313 patients after half a year of anti-leprosy treatment ( 12 ). It also explains whythe prednisolone dosage in the period 1974-1978 could slowly be reduced in the courseof antileprosy treatment.

The fact that DDS was continued in fulldosage during the antireaction treatmentafter 1974 did not seem to have any effectupon the severity of the reaction, contrary tothe view of some leprologists ( I- 7 ).

The antireaction treatment in BT patientscan be shorter than in BL patients, probablybecause of the lower antigenic load of BTpatients. The average duration of about sixmonths is only slightly longer than the per-iod described by Consigli et al ( 3 ) who es-pecially studied BT patients.

In the past four years more than 300 pa-tients with neuritis caused by reversal reac-tion have been treated with the prolongedsteroid treatment here described. No majorside effects were encountered, especially no"steroid dependence." About I% to 2% ofthe patients developed active pulmonary tu-berculosis. However, this is approximatelythe prevalence of this disease among thegeneral population in Ethiopia. The use ofsteroids in patients with chronic ENL wasmore hazardous; 10% to 20% developed activepulmonary tuberculosis (unpublished obser-vations). However, the question here re-mains whether tuberculosis predisposes toENL or was the result of the steroid treat-ment.

The prolonged steroid regime as here pre-sented has been shown in this study to bemore effective than a short-term steroidregime and it has been without serious sideeffects in Ethiopian borderline leprosy pa-tients. The differences in the results ob-tained by the different treatment regimescannot be explained by differences in thecomposition of the patient groups treated.There were no significant differences be-tween the groups with respect to sex, age,type and duration of leprosy, nor in the typeand the duration of the reversal reaction be-

fore antireaction treatment.It is now clear that when a reversal reac-

tion is detected in time (within three to fourmonths), the patient can be assured that hewill not become crippled. This should in-crease his trust in his doctor and his com-pliance with the treatment prescribed, whichis essential for any leprosy control scheme.Methods of applying these encouraging re-sults to rural leprosy control programs de-serve careful consideration.

SUMMARYBorderline leprosy patients with a reversal

reaction were studied and short-term steroidtreatment compared with prolonged steroidtreatment using voluntary muscle testing(VMT) to assess the results. Prolonged ster-oid treatment was shown to be superior toshort-term treatment and free of harmful ef-fects. It is concluded that with the describedantireaction treatment, permanent nervedamage can be prevented, provided that thereversal reaction is detected in time (within3-4 months).

RESUMENSe estudid el efecto del tratamiento con es-

teroides durante periodos cortos de tiempo encomparacidn con el tratamiento esteroidal pro-longado en pacientes con lepra intermedia (bor-derline) en reaccidn reversa. Los resultados sevaloraron por la "prueba de los mdsculos volun-tarios" (PM V). Se demostrd que el tratamientoprolongado con esteroides es superior al trata-miento de corto tiempo, ademds de estar libre deefectos colaterales indeseables. Se concluye queel tratamiento antireaccional descrito, puede pre-venir el daiio nervioso permanente siempre ycuando la reaccidn reversa sea detectada a tiem-po (dentro de los primeros 3 a 4 meses).

RESUME

Des malades lepreux du groupe "borderline"qui ont prdsentd des reactions d'iversion ont fait('objet de cette etude. Deux traitements aux ste-roides ont ete compares en employant les testsmusculaires comme parainiqres: un traitementa court terme et un traitement prolonge. II estapparu que le traitement do longue duree (Ransuperieur au traitement plus court. Nos resultatspermettent de conclure qu'un traitement antird-actionnel bien conduit est en mesure de preve-nir des dommages nerveux permanents, pourvuque la reaction d'inversion soit detect& a temps(en dedans les 3 a 4 mois).

12^ International .lourtial of Leprosy^ 1979

Acknowledgments. We would like to acknowl-edge the cooperation of the registration depart-ment of the Addis Ababa Leprosy Hospital. Wethank the physiotherapy department for theirhelp, especially Miss Jean Watson and all ourcolleagues at ALERT . The study was made pos-sible by financial contributions from the Nether-lands I.eprosy Relief Association and the govern-ments of the Netherlands and Ethiopia.

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