See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/8896083

Treatment duration of reversal reaction: A reappraisal. Back to the past

Article  in  Leprosy review · January 2004

Source: PubMed

CITATIONS READS
36 70

1 author:

Bernard Naafs
Global Dermatology
154 PUBLICATIONS   1,916 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

Tropical dermatology View project

Leprosy View project

All content following this page was uploaded by Bernard Naafs on 15 August 2014.

The user has requested enhancement of the downloaded file.

 Lepr Rev (2003) 74, 328±336

Treatment duration of reversal reaction:

a reappraisal. Back to the past

BEN NAAFS
IJsselmeerziekenhuizen Emmeloord/Lelystad and Leiden University
Medical Centre (LUMC), The Netherlands
Instituto Lauro de Souza Lima (ILSL), Bauru, SP, Brazil
Regional Dermatology Training Centre (RDTC), Moshi, Tanzania

Accepted for publication 9 September 2003

Summary In this paper, earlier data on the length of prednisolone treatment are
re-examined. Based on those data and supported by the literature and the author's
own observations, it can be concluded that type I leprosy reaction should be treated
with prednisolone for a longer period than the 12 weeks, advised by the WHO. The
paper also warns against silent nerve damage that may occur when prednisolone is
discontinued early.

Introduction

The 7th WHO Expert Committee on Leprosy stated in June 19971 that `the crucial elements
in the management of leprosy reactions and thereby the prevention of disabilities, are early
diagnosis of reactions together with prompt and adequate treatment'. The committee also
stated that `most reactions and neuritis can be treated successfully under ®eld conditions by a
standard 12 weeks course of prednisolone'. The former statement on the importance of early
diagnosis cannot be overestimated. However the latter statement that most reactions and
neuritis can be successfully treated in 12 weeks is most likely to be incorrect.
Nerve damaging reactions are the cell-mediated type I leprosy reaction (reversal reaction,
RR) and the type II leprosy reaction (erythema nodosum leprosum, ENL), which seems to be
immune-complex driven (see Table 1 for criteria). Very little is known on the duration of
these reactions. It is assumed that a type I reaction lasts for months and a type II reaction for
weeks. The duration of the type II leprosy reaction; less than 1 week 18´7%, up to 2 weeks
32´4%, up to 3 weeks 18´6% and up to 1 month 29´3% was noted by Lara in 1924 at Cullion
leprosarium in the Philippines as described by de Souza-Araujo.2 However, ENL may reoccur
and become chronic, lasting for years.3,4
During the 15th World Leprosy Congress in Beijing in 1998,5 it became apparent that
no evidence-based treatment schedules were available for the treatment of these reactions.

Correspondence to: B. Naafs, Gracht 15, 8485 KN Munnekeburen, The Netherlands (e-mail: benaafs@dds.nl)

328 0305-7518/03/064053+09 $1.00 q Lepra

 Treatment duration of reversal reaction 329

Table 1. Criteria for reactions to be used for research or in the ®eld (proposed by B. Naafs, P. K. Das, W.
R. Faber and D. V. A. Opromolla)
A patient has a type I (reversal) reaction when he has the major criterion or at least two minor criteria
(without signs of ENL).

Major Pre-existing and/or new skin lesions become in¯amed, red and swollen.
Minor 1. One or more nerves become tender and may be swollen.
2. Crops of new (painless) lesions appear.
3. Sudden oedema of face and extremities.
4. Recent loss of sensation in hands and feet or signs of recent nerve damage
(loss of sweating, sensation, muscle strength) in an area supplied by a particular nerve.

A patient has a type II (ENL) reaction when he has the major criterion or at least three minor criteria.

Major A sudden eruption of tender (red) papules, nodules or plaques, which may ulcerate.
Minor 1. Mild fever, the patient is unwell.
2. Tender enlarged nerves.
3. Increased loss of sensation or strength.
4. Arthritis.
5. Lymphadenitis.
6. Epididimo-orchitis.
7. Iridocyclitis or episcleritis.
8. Oedema of extremities or face.
9. Positive Ryrie or Ellis test.

Evidence based at that time meant, `double-blind, placebo controlled studies'. However, the
understanding of `evidence-based' has changed during the past few years, giving more credit
to careful monitoring of individual patients and retrospective studies.

Type I leprosy reaction (reversal reaction): treatment

Steroid treatment (prednisolone) is still considered the treatment of choice for the RR,6 and
the starting dose of 30±40 mg also leads to little discussion.7 However, the length of
treatment does.6,7
In 1950, Chaussinand8 in his textbook `La LeÁpre' commented that, a 4±7 day course of
injections with cortisol or ACTH has been used successfully, but the reactions usually
re-appeared once the treatment was stopped. Treatment with steroids was also a matter of
discussion during the 6th World Leprosy Congress in Madrid (1953). It was considered
effective but `rebounds' were feared.
Cochrane9 cited Cap Oliver in his textbook on leprosy, `Acute forms of neuritis
associated with dimorphous or tuberculoid reactions are best treated with corticosteroid
drugs, prednisolone 20±40 mg daily depending on the severity, and gradually decreasing the
dose corresponding to the stage of clinical resolution. Treatment given for 1 week to 1 month,
or occasionally longer is usually suf®cient to deal with the pain'. This treatment schedule
based on clinical observation was used by most leprologists, afraid as they were to use
steroids for prolonged periods. However, for some the cost was also an inhibitory factor.
Nevertheless, at the end of the 1950s, some leprologists tended to treat for longer treatment
periods.10
330 B. Naafs

In 1968, Goodwin published the voluntary muscle test (VMT) adapted for leprosy
patients.11 From that time onwards, it became possible to objectively assess motor nerve
function during treatment. Not long afterwards, Pearson introduced Weddell's graded bristle
test to assess sensory nerve function.12
Between 1968 and 1974, researchers at the All Africa Leprosy and Rehabilitation
Training Centre (ALERT) in Addis Ababa used two different regimens for treating RR.13
One regimen comprised 45±60 mg prednisolone daily tapered off over 1 month to 5 mg and
then continued with 5 mg for another month. The other regimen started with 15 mg and
tapered off to 5 mg in 1 month and continued at the same dose for another month. This
regimen was repeated once or twice when patients showed increased activity. Patients were
monitored carefully using the VMT. Retrospective analyses comparing the two regimens did
not reveal any difference in the outcome of treatment (Naafs, unpublished observations).
Pearson was one of the ®rst to adjust treatment to an objective change in the nerve
function parameters and consequently he gradually lengthened the treatment period. With
the introduction of EMG equipment at ALERT in 1974 by Baar, motor nerve conduction
velocity could be used in addition to VMT and sensory testing as a parameter of nerve
involvement.14,15
From 1974 onward, patients at ALERT with an RR were started on 30±40 mg
prednisolone once daily, which was then after 1 month reduced over a 2±3 month period
to 20±25 mg. Thereafter, the prednisolone dose was reduced by 5 mg once monthly.13 The
dose was increased again to the previous dose when nerve function parameters deteriorated.
In a few instances, the increase was 10 mg instead of 5 mg. This was also done when
improvement came to a halt after reducing the dose. It was observed that 15±20 mg
(6 0´30±0´35 mg/kg) was the critical dose of prednisolone to control an RR after the initial
period. The total duration of treatment was 4±9 months for BT patients, 4±14 months for BB
patients and 6±20 months for BL patients.13 These treatment durations are in accordance with
the experience of Rose and Waters16 and with recently reported data on the length of RR by
Li Huan-Ying17 (Table 2).
The ALERT prednisolone treatment used before 1974 was compared with the predniso-
lone treatment used after 1974 using the VMT as parameter. Patients were followed-up for 3
years. Anti-leprosy treatment was 200±300 mg dapsone once weekly before 1974. In the ®rst
2 weeks of anti-reaction treatment dapsone was discontinued, thereafter restarted and
increased slowly again. After 1974, patients received 5, 50 or 100 mg dapsone daily and
the treatment was not interrupted, only one BL patient received clofazimine (Naafs,
unpublished observations).
In Table 3, it can be seen that the number of patients that deteriorated after the ®rst months
despite the treatment was much higher during 1968±1974 than it was during 1974±1978.13 It

Table 2. Length of RR of patients on MDT reported by Li Huan-Ying17

Duration in months

<3 4±6 7±12 13±24 25±48

BT 8 5 2 3 0
BB 2 2 1 0 1
BL 21 9 30 1 1
 Treatment duration of reversal reaction 331

Table 3. Comparison of treatment results for the periods 1968±1974,13 1974±197813 and
1994±199523

Time at which maximum

nerve damage was
observed ALERT13 ALERT13 WHO23

25 patients 23 patients 16 patients treated

1968±1974 1974±1978 1994±1995
Start or after 1 month 8 19 8
At 3 months 6 4 1
At 6±12 months 11 0 7

is obvious that the process of nerve damage in most patients was not arrested by the short
period of prednisolone treatment. When a longer period of prednisolone treatment was used,
very few patients deteriorated once the treatment was initiated and none after 3 months.
The average of the VMT de®cits during and after prednisolone treatment is shown in
Figure 1.13 During severe reactions (initial VMT de®cit > 12) during 1968±1974, there was
no improvement in the average value during the ®rst half year, though there was a gradual
improvement thereafter. This could be explained by assuming that the reaction had settled,
the natural course during anti-leprosy treatment as con®rmed by Li Huan-Ying.17 During
1974±1978, there was a continuous improvement from the start of prednisolone treatment
and that continued for at least 2 years. The average duration of anti-reaction treatment was
6±9 months, which is slightly longer than the period described by Concigli et al.10 However
they especially studied BT patients.
It is unlikely that the type of anti-leprosy treatment had a major in¯uence on the course of
the reaction in patients with severe nerve involvement except by eliminating the bacilli and
therewith the antigens, a major trigger for reaction. Among patients with a mild reaction,
there was the impression that the ones who received the higher dose of dapsone did better than
the ones on the lower dose. However, the dose of dapsone did not in¯uence the main outcome
of that study (Naafs, unpublished observations). The message of the study was that the
treatment must be prolonged and preferably personalized.13
It was clear that in the ®eld individually tailored anti-reaction treatment was not feasible.
Therefore, ®xed and semi-®xed, schedules were recommended and implemented.18±20 The
results in general were good, although no long-term follow-up was performed at that time.
WHO advised a shorter treatment regimen,1 in which the prednisolone dose stayed above
the crucial dose of 15±20 mg only during the ®rst 2±3 months. The results at the end of the
treatment seemed to be good.21 However, there was no proper follow-up of the patients
during the post-treatment period. Becx-Bleumink et al. using a similar treatment regime
found that during follow-up at least one-third of the BL patients deteriorated after the
prednisolone treatment.22
Based on the paper by Naafs et al.,13 the editorial of Rose and Waters16 and the data
supplied by Li Huan-Ying17 it was unlikely that such a short treatment could be effective
in the long run. Therefore patients who had been treated with the WHO advised regimen
and had been followed-up with VMT were reassessed 3±8 months after treatment with
prednisolone was stopped.23 Data of 16 evaluable patients are shown in Figure 26,23 and in
Table 3.23
332 B. Naafs

Figure 1. Improvement in borderline patients with neuritis during a 3-year follow-up period. Short-term steroid
treatment compared with prolonged steroid treatment (reprinted from13).

The graph in Figure 2 shows that although the VMT de®cit improved markedly during the
prednisolone treatment in 15 of the 16 patients; nine of them deteriorated subsequently to
values not much different from the pretreatment values. The average result in VMT de®cit
before and 6 months after treatment was about the same.
In Table 3, the result of the WHO treatment (1994±1995)23 is compared with the result of
the treatment preferred at ALERT before 1974 and with those of the patient tailored-
treatment in the period 1974±1978.13 It can be seen that seven of the patients on WHO
treatment had a higher VMT de®cit 9±12 months after treatment than before treatment. These
results were better than those obtained with the short 1±2 months treatment with prednisolone
before 1974 at ALERT, but fell far short of those obtained by the longer duration patient-
tailored one. This small study showed clearly that at least half of the patients in type I leprosy
reaction would bene®t from prolonged prednisolone treatment.
There are more data available to support this statement. Nicholls remarked at the Asian
Leprosy Congress in Agra, India (2000) in a workshop on nerve damage that recurrent
reactions were frequent. Most of the participants at that session concurred with him. The
author of this paper was one of the exceptions. He has personally treated (patient-tailored)
and followed-up between 1974 and 2003 an estimated 400 patients with type I leprosy
reaction over a period of at least 3 years using VMT and graded sensory bristles; moreover,
electrophysiological parameters in about 200 of them. Less then 2% of the patients who
 Treatment duration of reversal reaction 333

Figure 2. The course of nerve function during reversal reaction treated by prednisolone, measured in arbitrary units.
The larger the value, the more damaged the nerves. Each line represents a single patient; *One patient assessed 3
months after completing prednisolone treatment (reprinted from 6 and 23).
334 B. Naafs

followed the recommended treatment had a recurrent reaction (Naafs, unpublished observa-
tions). His prednisolone treatment, however, often exceeded the 6 months, whereas the
treatment the other participants referred to were shorter.
Recurrent RR was seen before the introduction of WHO/MDT in patients who developed
dapsone resistance (Naafs, unpublished observation). Some of the patients developed a
recurrent reaction after the introduction of MDT, indicating that probably they had been
resistant to dapsone before. A recurrent RR was frequently noted in patients who had
prematurely stopped their prednisolone treatment, similar to the present-day situation with
WHO advised steroid treatment. After the introduction of MDT, recurrent RR was
occasionally seen in MB patients released from anti-leprosy treatment. This was probably
due to the disappearance of the protective effect of dapsone.24,25 Recently it has also been
seen in patients infected with HIV who received HAART (Highly Active Anti-Retroviral
Treatment) (Naafs, unpublished observation).
Thacker et al.26 studied leprosy patients electrophysiologically during and after reactions.
The patients were treated with prednisolone over a 6-week period. They observed signi®cant
improvement during treatment, but deterioration after prednisolone was stopped. Li Huan-
Ying17 reporting on the duration of a RR found that only 39´6% subsided in less than 3
months and 62´1% within 6 months. In 22´2% of the BL patients it was found that the RR
lasted at least 7±12 months. These data con®rm the data of Naafs et al.13
Other evidence supporting prolonged treatment with prednisolone was reported recently
by Little et al.,27 who observed that there was a continuing Th1 cytokine activity even 180
days after the start of prednisolone in some of the patients at follow-up. They used
immunohistochemistry. At the 16th International Leprosy Congress in Salvador, Bahia,
Brasil, P. S. Rao presented a controlled trial of different prednisolone dosages and durations
in type I reactions, based on a protocol written by Lienhardt, which showed clearly that the
longer duration was statistically better than the shorter duration, but that the initial dose
(60 mg compared to 30 mg) was not signi®cant.7 Based on this and on recent data from Nepal
(Tripod 1): `a 3±4 month prophylactic treatment with steroids in MB patents starting on MDT
does prevent nerve function impairment (NFI) only at 4 and 6 months but the effect is not
sustained at 12 months',28 together with information from Ethiopia and Nepal29,30 also
reported and discussed during the congress, Lockwood remarked that it may be that the
treatment of RR has to be prolonged.
Public health oriented leprologists recommend that patients should be instructed about the
signs and symptoms of reactions and when to return for assessment. This has become a
general WHO policy. However, the investigation of Otters and Gieteling23 showed that
hardly any of the patients who had deteriorated after the treatment with prednisolone had
been discontinued, would have reported back on their own account. Because they had not
noticed any pain and because the deterioration had been very gradual (silent nerve damage)
and did not bear resemblance with the `disease' they had been treated for in the past. Hence
there was no reason for them to report. Silent nerve damage is considered to be a major
problem,31,32 especially how to detect and treat it. However, a number of clinicians reported
at the World Leprosy Congress in Salvador that improvement in function may occur after
prolonged treatment with steroids.32

Acknowledgement

Dr Bob Tank advised on the use of the English language.

 Treatment duration of reversal reaction 335

Addendum

Treatment proposal for type 1 leprosy reactions, prednisolone once daily in the morning:

Paucibacillary Multibacillary

40 mg 2 weeks 30 mg 1 month
30 mg 2 weeks 25 mg 2 months
25 mg 1 month 20 mg 3 months
20 mg 2 months 15 mg 2 months
15 mg 1 month 10 mg 2 weeks
10 mg 2 weeks 5 mg 2 weeks
5 mg 2 weeks
Total 6 months Total 9 months

References
1
WHO Expert Committee on leprosy. Technical Report Series 874, 1998.
2
De Souza-Araujo HC. Febro leprotica. In: A lepraÐEstudos realisados em 40 paizes (1924±1927). Trab. do Inst.
Oswaldo Cruz, Rio de Janeiro 1929, pp. 179±183
3
Sampaio SAP, ProencËa NG. Tratimento da reacËao leproÂtica pela talidomide. Rev Paul Med, 1966; 68: 301.
4
Imkamp FM. A treatment of corticosteroid-dependent lepromatous leprosy in persistent erythema nodosum
leprosum. A clinical evaluation of G30320 (B663). Lepr Rev, 1968; 39: 119±125.
5
Lockwood D, Scollard DM. Report of workshop on nerve damage and reactions. Int J Lepr, 1998; 66: 498±499.
6
Naafs B. Treatment of reactions and nerve damage. Int J Lepr, 1996; 64: S21±28.
7
Rao SP. Paper presented at the 16th ILA Congress, Salvador, Bahia, Brasil, 2002.
8
Chaussinand R. In: La leÁpre. Expansion Scienti®que FrancËaise, Paris, 1950.
9
Cochrane RG. Neuritis in leprosy. In: Cochrane RC, Davey TF (eds) Leprosy in theory and practice, 2nd edn.
Wright, Bristol, 1964, pp. 410±417.
10
Consigli CA, Biagini R, Vasquez C. El tratamento de la reaccioÂn leprosa con prednisona. Leprologia (Buenos
Aires), 1958; 3: 16±20.
11
Goodwin CS. The use of the voluntary muscle test in leprosy neuritis. Lepr Rev, 1968; 39: 209±216.
12
Pearson JMH, Weddell G. Changes in sensory acuity following radial nerve biopsy in patients with leprosy. Brain,
1971; 94: 43±50.
13
Naafs B, Pearson JMH, Wheate HW. Reversal reaction: the prevention of permanent nerve damage. Comparison
of short- and long-term steroid treatment. Int J Lepr, 1979; 47: 7±12.
14
Naafs B, Pearson JMH, Baar AJM. A follow-up study of nerve lesions in leprosy during and after reaction using
motor nerve conduction velocity. Int J Lepr, 1976; 44: 188±197.
15
Naafs B, Tamru Dagne. Sensory testing: a sensitive method in the follow-up of nerve involvement. Int J Lepr,
1977; 45: 364±368.
16
Rose P, Waters MFR. Reversal reactions in leprosy and their treatment. Lepr Rev, 1991; 62: 113±121.
17
Li Huan-Ying. Analysis of reversal reaction in leprosy patients following ®xed duration MDT. Paper at the Asian
Leprosy Congress in Agra, 2000.
18
Naafs B. Therapy of neuritis during reactions in leprosy. Health Coop Papers 1981, pp. 65±70.
19
Touw-Langendijk EM, Brandsma JW, Andersen JG. Treatment of ulnar and median nerve function loss in
borderline leprosy. Lepr Rev, 1984; 55: 41±46.
20
Kiran KU, Stanley JN, Pearson JMH. The outpatient treatment of nerve damage in patients with borderline leprosy
using a semi-standardized steroid treatment regimen. Lepr Rev, 1985; 56: 127±134.
21
Bernink EH, Voskens JE. Study on the detection of leprosy reactions and the effect of prednisone on various
nerves. Lepr Rev, 1997; 68: 225±232.
22
Becx-Bleumink M, Berhe D, `t Mannetje W. The management of nerve damage in leprosy control services. Lepr
Rev, 1990; 61: 1±11.
23
Otters JBM, Gieteling MJ. A follow-up study of 21 outpatients treated with a short-term steroid regimen. Term
paper, University of Rotterdam, 1995.
24
Barnetson RStC, Pearson JMH, Rees RJW. Evidence for prevention of borderline leprosy reactions by dapsone.
Lancet, 1976; ii: 1171±1172.
336 B. Naafs
25
Naafs B, Lyons NF, Madombi L, Matemera BO, Ellis BPB. Short-term WHO-advised multiple drug treatment of
paucibacillary leprosy patients. Ind J Lepr, 1986; 58: 348±353.
26
Thacker AK, Chandra S, Mukhija RD, Sarkari NB. Electro-physiological evaluation of nerves during reactions in
leprosy. J Neurol, 1996; 243: 530±535.
27
Little D, Khanolkar-Young S, Coulthart A, Suneetha S, Lockwood D. Immunohistochemical analysis of cellular
in®ltrate and gamma interferon, interleukin-2, and inducible nitric oxide synthease expression in leprosy type I
(reversal) reactions before and during prednisolone treatment. Infect Immun, 2001; 69: 3413±3417.
28
Anderson AM, Van Brakel WH, Withington SG, Croft RP, Nicholls PG, Richardus JH, Smith WCS. Prophylactic
steroids to prevent nerve function impairment in leprosy: a randomised ontrolled trial (TRIPOD 1). Book of
abstracts, 16th ILA Congress, Salvador, Bahia, Brasil, 2002, OCA 23: 63.
29
Marlowe SNS, Knuulilla J, Herm F, Bizuneh E, Leekassa R, Lockwood DNJ. Clinical response to cyclosporine a
treatment in severe leprosy type I reaction (T1R) patients in Nepal and Ethiopia. Book of abstracts, 16th ILA
Congress, Salvador, Bahia, Brasil, 2002, OCA 7: 59.
30
Hawskworth R, Marlowe S, Butlin R, Jacob K M, Macdonald M, Nicholls P, Lockwood D. Use of azathioprine in
the treatment of leprosy type 1 reaction. Book of abstracts, 16th ILA Congress, Salvador, Bahia, Brasil, 2002,
OCA 30: 65
31
Croft RP, Nicholls PG, Richardus JH, Smith WC. Incidence rates of acute nerve function impairment in leprosy.
Prospective cohort analysis after 24 months (The Bangladesh Nerve Damage Study). Lepr Rev, 2000; 71: 18±33.
32
Jiang J, Zhang GC, Wei WY. A ®eld trial of detection and treatment of nerve function impairment in leprosy.
Report from national POD project. Book of abstracts, 16th ILA Congress, Salvador, Bahia, Brasil, 2002, PCA 4;
139.

View publication stats