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Clinics in Dermatology (2016) 34, 37–50

Leprosy type 1 reaction


(formerly reversal reaction)
Bernard Naafs, MD, PhD a,⁎, Colette L.M. van Hees, MD b
a
The Foundation of Global Dermatology, The Netherlands
b
Department of Dermatology, Erasmus Medical Centre, Rotterdam, The Netherlands

Abstract Nerve damage leading to impairment and permanent disability is the major problem in the
course of a leprosy infection. Most of the damage occurs during two types of leprosy reactions, type 1
reaction (T1R) and type 2 reaction (T2R). Timely and adequate treatment may prevent this damage.
Particular T1R reactions, however, are often diagnosed too late and are even missed. Clinical symptoms
and warning signs are therefore covered, as are the immunology and pathophysiology of nerve damage. The
differences between upgrading and downgrading, old terms but still relevant, are explained. Methods to
detect reactions and to monitor their treatment are given. Triggering factors, the mechanisms of the reactions,
including autoimmunity, and the presence of physical compression are discussed. Treatment over the years is
placed in its context, and based on this information a treatment schedule is recommended.
© 2016 Elsevier Inc. All rights reserved.

Introduction The most important causes of nerve damage are the acute
episodes in the chronic course of the disease, caused by changes
Nerve damage leading to impairment and permanent in the host immune response against Mycobacterium leprae
disability is the major problem in the course of a leprosy antigenic determinants, known as reactions; there are type 1
infection. Were it not for these, leprosy would be a rather leprosy reaction (T1R), or reversal reaction, and type 2 leprosy
innocuous skin disease. To this day, however, leprosy is still reaction (T2R), also called erythema nodosum leprosum (ENL).
one of the most feared diseases, often associated with serious The first occurs in borderline leprosy (BL) patients and the latter
social repercussions. It has been stated that there is no in lepromatous patients.1,2
leprosy without nerve damage.
Nerve damage in leprosy may occur before antimyco-
bacterial treatment, during treatment, and even up to 30 years Type 1 leprosy reaction
after treatment in patients who are labeled cured.1,2 When it
occurs during or after treatment, it is frustrating for both the In the past, different names were used for type 1 reaction,
patient and the doctor. leading to disagreement among leprologists. As a result, for
quite some time, there was an Anglo-Saxon–French, a
⁎ Corresponding author. Spanish–Portuguese–South American, and an Indian
E-mail address: benaafs@hotmail.com (B. Naafs). school.2 At present, a common nomenclature and definition

http://dx.doi.org/10.1016/j.clindermatol.2015.10.006
0738-081X/© 2016 Elsevier Inc. All rights reserved.
38 B. Naafs and C.L.M. van Hees

is used: type 1 leprosy reaction (T1R). The term reversal reaction


(RR) is discouraged.
A reaction belongs to the normal course of leprosy as a
disease; however, treatment may precipitate or prevent it.3

Diagnosis of T1R 1,2,4,5

Skin involvement often accompanies nerve involvement


but may also precede or follow nerve damage. It is often the
skin involvement that brings the patient to a clinic, or ideally
to a dermatologist, although even this does not always
guarantee prompt diagnosis and treatment.6 Clinically, a
reaction may be suspected when there is increased
inflammation of preexisting skin lesions. Hypopigmented
or only slightly erythematous macules become red and swollen,
form plaques, and occasionally undergo ulceration (Figure 1).7,8
Crops of new lesions may suddenly appear in previously
clinically uninvolved skin.1,9,10 Sometimes, extensive edema of
the extremities or face may be present, in particular in BL
patients (Figure 2).1
Patients may complain of a burning, stinging sensation in
the skin lesions and verbalize aches and pains in the
extremities or in the face and loss of strength and/or sensory Fig. 2 Acroedema during T1R in a BL patient.
perception. They may suddenly start to drop things, or
stumble when walking. They also may develop blisters
without knowing the cause; however, contrary to patients
with T2R, they are not ill.11 necessary. These consist of mapping (drawing) the lesions,
Some patients with T1R have remarkably few complaints; which is tedious but worthwhile, and of careful assessment of
therefore, detection may be delayed or even missed. To nerve function (ie, autonomic, motor, and sensory function).
prevent permanent damage, objective clinical parameters are Note whether the hands and feet show atrophy, are sweating, or
have new dry areas. The appearance of dry areas or an increase
in size of these areas is often a first sign of an incipient reaction
(Figure 3). Nerves may become thickened and are tender on
palpation (Figure 4).9,12,13 The Tinel sign may become
positive; meaning that tapping on the nerve causes a tingling
pain, distally.13 The facial, ulnar, median, radial, peroneal and
tibial nerves should be assessed (Figure 5).

Fig. 1 Facial inflammatory plaques during T1R in a BL patient. Fig. 3 Dry smooth left hand as early sign of nerve damage.
Leprosy type 1 reaction 39

Table 1
Grade Characteristics
5 Full range of movement, normal strength and resistance
4 Full range of movement, less than normal strength
and resistance
3 Full range of movement, no resistance
2 Limited range of movement, no resistance
1 No visible movement, a muscle flicker can be palpated
0 Complete paralysis

Voluntary muscle testing

In the mid-1960s, a numerical system for use in leprosy


was developed to assess muscle strength, known as voluntary
muscle testing (VMT) (Table 1).14,15 When this test is
performed regularly and carefully, it assists in the early
detection of a reaction. Deterioration in VMT may precede
more obvious clinical signs; however, because the test often
is not sensitive enough, minimal damage may go unnoticed.
Fig. 4 Enlarged median nerve in type 1 reaction. When evaluating the facial nerve, ask the patient to close his
or her eyes lightly and watch for any flicker or movement
of an eyelid or a slight gap in the closure, which may
herald further damage. One must realize that when a patient
is asked to close the eyes firmly, such minimal damage may
pass unnoticed.

Sensory testing

A sensitive method is the assessment of sensory loss with


the graded sensory bristle test. This was developed by
Maximilian von Frey (1852-1932) in 1896, originally using
horsehairs of various thickness and length. Today, standard-
ized nylon monofilaments are used. Graham Weddell
(1908-1990) in the mid-1930s (Figure 6).16 This test was
later validated for use during the follow-up of nerve lesions
during leprosy reactions.17–19 Over the years, it has been
found to be a reliable, reproducible test,18–21 of which the
filaments are now standardized and generally known as
Semmes-Weinstein monofilaments.22
The graded bristle test can be performed by mapping areas
for sensory loss and by grading this loss, as is generally done
by physiotherapists involved in leprosy and diabetes control.
This test is prone to inaccuracy, because it is a tedious
and sensitive procedure. It can, therefore, only be used
effectively by experienced investigators under quiet condi-
tions. For the rushed clinician, it is easier to assess a small
defined area like the thenar for the median nerve, the
hypothenar for the ulnar nerve, and the plantar forefoot and
heel for the posterior tibial and common peroneal nerve. Care
must be taken not to assess within a skin patch when present.
Another useful sensory test, especially for the foot, is the
2-point discrimination test (moving or static), using a
Fig. 5 Palpation of nerves. (Courtesy Dr. Enrico Nunzi.) paperclip bent to a caliper. It is less sensitive than the graded
40 B. Naafs and C.L.M. van Hees

we feel that the 5-point scale should be used even under field
conditions, provided proper supervision and training is
continuously available (Table 2). The same applies for
sensory testing. Testing with a ballpoint on the hand and feet
is crude but helpful when properly done: The skin should not
be pressed, just slightly touched using the weight of the
ballpoint pen only, and no white dimple should appear.25
Graded bristle testing is very sensitive and the preferred
method when feasible. In the field, the testing of the thenar
area, hypothenar area, and foot has been shown to be possible
by a well-trained and supervised field staff.24

Testing in specialized centers

A more sophisticated method to evaluate nerves is


electrophysiology, conduction time, and the recorded shape
of the action potential measured several times during
diagnosis and treatment. Novel electropathophysiologic
characteristics of the ulnar nerve during type 1 and 2 leprosy
reactions provided new insights for treatment, expected
recovery, and the general prognosis in each type of
reaction.26 In T1R there is usually conduction delay, and
temporal dispersion can be seen; in T2R, a conduction block
may develop.⁎ Detection of these nerve conduction changes
can guide treatment and distinguish between both types
of reactions.26
Laboratory tests that may be useful for the follow-up of
Fig. 6 Bristles for graded sensory testing according to Pearson. reaction treatment include the following:

1. Levels of cytokines (eg, interferon γ, tumor necrosis


factor α, interleukin (IL) 1, IL-2, IL-6, IL-10, IL-13, and
bristle test for sensory loss mapping of the hand but nearly IL-17).27–31
as sensitive as the graded bristles when used on the forefoot 2. Measurement of the acute-phase response.29
or heel. Importantly, for the time-pressed dermatologist, it is 3. Measurement of macrophage activation products such
less time consuming.23 as neopterin29,32 and chitotriosidase.33
4. Levels of antibodies against specific M leprae antigens
Testing in the field (phenolic glycolipid 1).29,34
5. Levels of CXC-ligand 10.35
In the field, extensive sensory testing and VMTs are out 6. Testing of the cell-mediated immunity (CMI) with
of reach; however, limited testing has been found to be lymphocyte transformation tests and migration inhibition
possible.24 Experience has been gained with VMT of the tests.36
orbicularis oculi for the facial nerve, the opponens pollicis
brevis for the median nerve, the abductor digiti minimi for At present, most of these tests are not useful for detecting
the ulnar nerve, and the dorsal flexion of the foot for the a reaction early, and they are not commonly available. Even
peroneal nerve. Because the 3-point scale, as recommended histopathologic and immunopathologic examinations are
by the World Health Organization (WHO), is rather crude, often only of limited help.37 It is still the clinician who, by
careful observation and simple clinical tests, has to detect the
reaction in time.
Table 2
Grade Characteristics
S (Strong) Able to perform the movement ⁎
Conduction block: A reduction of proximal compound motor nerve
against full resistance
action potential (CMAP) area/amplitude of at least 20% (usually N50%)
W (Weak) Able to perform the movement but
compared with distal CMAP area/amplitude. The duration of the proximal
not against full resistance CMAP should not increase by N 20% (see temporal dispersion). Temporal
P (Paralyzed) Not able to perform the movement at all dispersion: A reduction in proximal CMAP amplitude compared with distal
CMAP amplitude when the proximal CMAP duration increases by N 20%.
Leprosy type 1 reaction 41

Differential diagnosis of T1R versus T2R 11 (suppressor/cytotoxic) cells increases.1 Interestingly, the
interplay between CMI and the humoral arms of host
Sometimes, especially in BL patients, it is difficult to immunity can further be appreciated by studying HIV and
discern a T1R from a T2R. The reactions may even occur leprosy coinfection. During active HIV infection, not much
together or one after the other; however, some signs and clinical leprosy is seen due to absence of CMI. When
investigations may be of help in the differential diagnosis. antiretroviral treatment is given, a subclinical leprosy
T2R is a generalized disease, affecting not only the skin infection becomes clinical, often as a T1R (an immune
and nerves but also other organs, such as joints, lymph reconstitution inflammatory syndrome [IRIS]).50 This type
nodes, and liver. In T1R these are seldom involved. The of reaction may also be seen after pregnancy,51 starvation,
patient may be ill (during a T1R the patient usually is not) and immunosuppressive therapy.52–54
and may have a raised temperature and erythrocyte T1R is a damaging occurrence that produces bactericidal
sedimentation rate, and even proteinuria. The skin lesions and tissue-damaging T-cell reactivity; however, it is
in T2R are usually tender; those in T1R are not. The lesions recognized that many patients suffering from a T1R recover,
in T1R may have sensory loss compared with the though with remnant tissue damage. The question arises
surrounding skin; in T2R this is usually not the case. whether these T-cell subsets play a balancing act with a key
When palpated, a T2R plaque consists of confluent papules role for Th1/Th17 cells both in exacerbation and remission.31
and nodules, whereas in a T1R the lesions feel more It is still not known which antigens or antigenic
homogeneous. Both T2R and T1R lesions may ulcerate, but a determinants are responsible for a T1R.1,47 Neither is the
smear from a T2R lesion shows predominantly polymorphs, orchestration of the cytokines and chemokines known,
that of a T1R lesion predominantly lymphocytes. though a great number of them have been identified;
Two older tests may be of help: moreover, the events may compartmentalize. What happens
in different places in the tissues is often different from that
1. The Ryrie test: Stroking the sole of the foot of a patient which occurs in the blood.46
with T2R with the back of a reflex hammer elicits a During a T1R, the peripheral blood lymphocytes show an
burning pain. When these patients walk, they look as if increased immune response toward M leprae antigens.55,56
they are walking on hot coals.24 When the reaction subsides, the immune response de-
2. The Ellis test: Squeezing the wrist during T2R elicits a creases55,56; however, which of the M leprae antigens, let
painful reaction; this does not occur during a T1R, alone which antigenic determinants, are involved is still
unless the radiocutaneus nerve is tender.24 unknown. Heterogeneity has been found, not only between
3. The motor nerve conduction velocity test: T1R different patients but also in the course of time in one patient,
shows only temporal dispersion, and T2R may also when the maximum CMI response changes from one antigen
show a conduction block.26 to another.57
Because M leprae are very difficult to find in paucibacillary
leprosy patients, especially in those with a T1R, autoimmune
phenomena have been implicated in the reactional process.
Immunology and pathology 2,5 Human nerves and skin have a great number of antigenic
determinants in common with M leprae (Figure 7).58–63
Histopathologically, the lesions have all the characteristics Many of those antigenic determinants are on heat shock
of a delayed-type hypersensitivity reaction.38 proteins (HSPs) (Figure 8).60–64 These can be found, in
In the initial lesion, only a mild extracellular edema may particular, in macrophages and epithelioid cells of granulo-
be noticed, with some proliferation of fibroblasts and a mild matous diseases such as sarcoidosis, necrobiosis lipoidica,
increase in the number of lymphocytes in the leprosy and granuloma annulare.62 For tuberculosis and other
granuloma.1,39 Later, there is a further increase in the edema mycobacteria, the same applies.65,66 In animal models,
and a change in the cellular composition in and around the M leprae–primed macrophages attack the Schwann cells, not
epithelioid cell granuloma due to an influx of lymphocytes only in the presence but also in the absence of detectable
that are mainly of the CD4 subtype, especially of the type 1 M leprae.67 It also has been observed in vitro that T cells that
helper T cell (Th1) class.37,40–44 When using methods for reacted with M leprae also reacted with components of
detection of mRNA, besides interferon γ the production of Schwann cells. Most leprosy patients have antibodies against
IL-2 and tumor necrosis factor α are found to be increased, nerve components.68
which confirms a shift to the Th1 subtype during the
reaction.45–47 Possibly due to this shift, humoral immunity Upgrading and downgrading reactions2,5
during a T1R appears to be diminished,47 though B cells are
present48,49; however, a shift to Th2 activity may also occur In the presulfone era, patients became less bacilliferous or
in the course of a reaction because there is an increase in even “cured” after an exacerbation of their leprosy.69 As a
mRNA for IL-4 in some of the lesions.37,43,44 During a result, they usually suffered from nerve damage. Patients
reaction and when it subsides, the relative number of CD8+ who shifted toward the tuberculoid end of the spectrum were
42 B. Naafs and C.L.M. van Hees

because during effective antibacterial treatment, no bacterial


multiplication was expected; thus, the term reversal reaction.
The concept, however, was never abandoned entirely.
Reactions still occurred in untreated and relapsing patients,77
and some pathologists had the strong impression that when a
reaction occurred they observed the appearance of, or a
temporary increase in, the number of M leprae, some of which
were solid staining, even in treated patients.78–80 The concept
became even more relevant with the introduction of multi-
ple-drug treatment by the WHO. Reactions now did not only
occur before treatment and during treatment but also after
antimycobacterial treatment.81–84 Reactions after treatment
became very difficult to discern from a relapse.77,84–86 An
increase in the number of solid-staining bacteria could
occasionally be observed, only to disappear after the reaction
settled.81 This was explained by assuming that this late
reaction had been effective in clearing the bacillary load, thus
an upgrading reaction.87 After the decline in the number of
bacilli with effective antimycobacterial treatment, enough of
the CMI had been restored to deal with newly multiplying
bacteria.87
Interestingly, the same authors who noticed an increase in
bacterial load during a reaction occurring during dapsone
monotherapy and during late T1R hardly observed this
phenomenon during multidrug treatment.77,81
Initially, to explain the disappearance of bacilli during one
Fig. 7 Mycobacterium leprae antigenic determinants in normal
type of reaction and not during the other, the concept of
skin and nerve stained by polyclonal M leprae antibodies.
protective immunity and nonprotective delayed-type hyper-
sensitivity was introduced.31,88–90 When the reaction was
considered to have an upgrading event; had they become directed against certain antigens, the bacteria were killed.
more lepromatous, a downgrading event. The original When it was directed against others, there was tissue damage,
publications mention regression and lepromatous transfor- but no damage to the bacteria. This concept, however, was
mation.69–73 increasingly challenged. In this respect, discrete T-cell
When sulfones became available, the occurrence of subsets and mycobacterium antigenic determinants appear
exacerbations or pseudoexacerbations of the disease after to control the clinical and immunologic spectrum of leprosy.
the introduction of treatment was observed,74–76 leaving T cells (probably together with the participation of antigen
the patients more damaged but with a decreased bacillary load. presenting cells and B cells), within the adaptive immunity,
The term reversal reaction was coined for these phenomena. play the pivotal role in both protective immunity and in
Many discarded the concept of a downgrading reaction, dictating the pathology.31 Another explanation that was
proposed is that, during an upgrading reaction, the immunity
is directed against antigenic determinants that are essential
for the bacterium to survive and that during a downgrading
reaction the reaction is directed against antigenic determi-
nants of secreted antigens, remnants of dead and dying
bacteria, or even antigenic determinants of the host that the
host has in common with M leprae.84
A third concept, stating that in both upgrading and
downgrading reactions the same antigenic components may
be involved, is the most likely one. In this concept, enhanced
CMI stimulated by bacterial or human host antigenic
determinants competes with a suppressive effect induced
by others.91,92 The orchestration of the cytokines, which
result from these immunologic events, is likely to be
responsible for the final effect, upgrading or downgrading.
Fig. 8 Leprosy granuloma stained with antimycobacterial heat An observation supporting this concept is the finding that
shock protein 65. different antigenic determinants induce a different cytokine
Leprosy type 1 reaction 43

profile in different individuals depending on the genetic in the skin with massive granuloma formation with
makeup and immunologic history of those individuals, occasional colliquation and abscess formation. Further into
including their contact with environmental microorgan- the borderline range these features are usually less distinct
isms.42,92–96 It should also be realized that events may differ and often even absent. Often only edema is observed.1,101
from site to site in the tissues. Damage to cutaneous and subcutaneous nerves causes loss of
sensation in the affected areas and loss of autonomic nerve
function such as sweating and the regulation of the vascular
Nerve damage 1,2,28,97,98 tone; however, it is the damage to the peripheral nerve trunk
that is the major consequence of a T1R. This damage is
Neuritis is a common occurrence during T1R. Frequencies partly caused by immunologic reactions, but mechanical
are cited between 43% and 73%.99,100 Nerve damage may factors are also involved.28,96–98,101–105
occur at three levels: At the level of the skin nerve endings, at During a T1R, inflammation and consequently edema
the level of the subcutaneous nerves, and at the level of the occur in the nerve, as they occur in the skin. The reaction
nerve trunks. leads to edema located within the interstitial tissues of the
Histopathologic examination of reactional tuberculoid perineurium and endoneurium. The perineurium, which is
leprosy finds granuloma formation high in the dermis and largely impermeable for fluids, forms a rigid compressing tube
dermal papillae. The granulomatous infiltrate destroys the around the expanding endoneurium. The resulting pressure
nerve endings in the papillae and sometimes erodes the increase within the nerve leads to axonal compression.
epidermis. It is likely that the driving forces behind these As consequence, there is a loss of conducting nerve fibers
damaging reactions are antigenic determinants in the and thus loss of muscular strength and peripheral sensation.
epidermis and in the peripheral nerve endings that are The intra-axonal flow, which transports nutrients from the
similar to those of the M leprae antigens. The reaction could cell to the peripheral nerve ending, is interrupted and sooner
be an autoimmune phenomenon.58–63,98 or later the peripheral nerve fiber dies and is destroyed
In borderline leprosy, the nerves in the lower dermis and (Figure 10).98,101
especially those located around the adnexa are most often When the pressure and the tension along and within the
involved. Granuloma formation can be seen in and around perineurium increase, there is an increase in the pressure
these nerves together with a proliferation of Schwann cells in exerted on the blood vessels that transverse obliquely
and around the perineurium. Damage can be attributed to through the perineurium. The venules with relatively low
compression and destruction of nerve fibers by the pressure are compressed more than arterioles with higher
epithelioid granuloma (Figure 9). During the reactional pressure. The compression of the venules will lead to a
episode, there is a further influx of immunocompetent cells higher pressure in the capillaries of the endoneurium, which
with edema formation and expanding granuloma. This may start “leaking” and thus increase the pressure in the
contributes further to nerve damage, especially when endoneurium (Figure 11).98,101 With ultrasound and color
extra-cellular edema accumulates inside the thickened Doppler, these phenomena can be visualized.106 This
perineural and epineural sheaths converting it into a rigid “venostatic edema” is able to maintain itself even when the
compressing tube, compromising the axons inside. immunologic events subside.101,107
The mechanisms that occur in nerve trunks and larger A study on nerves in patients experiencing both types of
subcutaneous nerves are more complicated. At the tubercu- reactions found that the nerve conduction changes were more
loid end of the spectrum, these processes are similar to those pronounced in nerves of patients with T1R compared with
patients with T2R.108 Before treatment, pathologic changes
of the ulnar nerve are predominantly found across the elbow
and less commonly along the forearm or distally at the wrist.
There is both demyelination and edema. The improvement in
conduction velocity and action potential after the first week
to first month is most likely due to the reduction of this
edema.101,108,109
In the T1R, diffuse subacute and chronic segmental
demyelination at the site of lesion leads to temporal
dispersion. The segmental demyelination is analogous to
chronic compression (entrapment syndrome). The mechanical
forces act quietly within anatomic tunnels as a consequence of
the chronic inflammation during a T1R, leading to a restriction
of gliding at the entrapment sites. The Ranvier node becomes
disconnected and the myelin loses its lamellar structure,
followed by demyelination and remyelination.110 In leprosy,
Fig. 9 Nerve compressed and infiltrated by leprosy granuloma. these compression phenomena are related to nerve
44 B. Naafs and C.L.M. van Hees

Fig. 10 Nerve damage due to a vicious circle effect during compression.

enlargement due to intraneural edema in the anatomic Schwann cell during the subacute inflammation occurring
tunnels.102,104 This insidious entrapment plus inflammation, during a T1R. Temporal dispersion improvement continues
if not treated, may lead to axonal loss in varying degrees. In the during the reduction of steroid treatment over time provided
T1R group, the temporal dispersion improved over time the steroids are not discontinued too quickly.26
(Figure 12), following the same curve pattern as the changes in
the cellular infiltrate and cytokines profile during steroid
treatment as indicated by an immunohistopathologic study of Treatment
the T1R skin lesions.111,112 The concordance between the
improvement of the cytokine profile and cellularity and the Steroid treatment (prednisone/prednisolone) with a start-
motor nerve conduction data indicate a high specificity of this ing dose of 30 to 40 mg is still considered the treatment of
parameter for the inflammatory demyelination in leprosy. choice for T1R113; however, the duration of the treatment is a
Temporal dispersion is associated with the involvement of the matter of debate.112,114

Fig. 11 Venostatic edema due to compression of blood vessels in the perineurium


Leprosy type 1 reaction 45

Fig. 12 Nerve conduction studies before (above) and after (below) T1R steroid treatment. (courtesy of dr José Garbino)

History Goodwin published the VMT adapted for leprosy patients.14


From that time onward, it became possible to objectively
In 1950, Chaussinand in his textbook La Lėpre
assess motor nerve function during treatment. Not long
commented that a 4- to 7-day course of cortisol or
afterward, Pearson introduced Weddell's graded bristle test
adrenocorticotropic hormone injections had been used
to assess sensory nerve function.118
successfully for reactions, but the reactions usually reap-
Between 1968 and 1974, researchers at the All Africa
peared once the treatment was stopped.115 Treatment with
Leprosy and Rehabilitation Training Centre (ALERT) in
steroids was also a matter of discussion during the sixth
Addis Ababa, Ethiopia, used two different regimens for
World Leprosy Congress in Madrid (1953). It was considered
treating T1R.119 One regimen comprised 45 to 60 mg
effective, but “rebounds” were feared.
prednisolone daily tapered off over 1 month to 5 mg and
Cochrane cited Cap Oliver in his textbook on leprosy116:
then continued with 5 mg for another month. The other
“Acute forms of neuritis associated with dimor- regimen started with 15 mg and tapered off to 5 mg in 1
phous or tuberculoid reactions are best treated with month and continued at the same dose for another month.
corticosteroid drugs, prednisolone 20-40 mg daily These regimens were repeated once or twice when patients
depending on the severity, and gradually decreasing the showed increased activity. Patients were monitored carefully
dose corresponding to the stage of clinical resolution. using the VMT. The average treatment lasted 2 to 3 months.
Treatment given for 1 week to 1 month, or occasionally There was no difference in outcome of these treatments.
longer is usually sufficient to deal with the pain.” In the 1970s, Pearson was one of the first to adjust
treatment to an objective change in the nerve function
This treatment schedule based on clinical observation was parameters, and consequently he gradually lengthened the
used by most leprologists, afraid as they were to use steroids treatment period.
for prolonged periods; nevertheless, in the late 1950s, some After the introduction of electromyography equipment at
leprologists implemented longer treatment periods, increasing ALERT in 1974, motor nerve conduction velocity could be
to a previous dose whenever nerve function parameters used in addition to VMT and sensory testing as a parameter
deteriorated.117 This was also still done, when, in 1968, of nerve involvement.17,120
46 B. Naafs and C.L.M. van Hees

From 1974 onward, patients at ALERT with a T1R were WHO advised a relatively short treatment regimen, in
started on 30 to 40 mg prednisolone once daily, which was which the prednisolone dose stayed above the crucial dose of
after 1 month reduced over a 2- to 3-month period to 20 to 15 to 20 mg only during the first 2 to 3 months, and provided
25 mg. Thereafter, the prednisolone dose was reduced by 5 blister packs.125 The results at the end of the treatment
mg once monthly.119 When the improvement came to a halt seemed to be good126; however, there was no consistent
after reducing the dose, it was increased by 5 mg and follow-up of the patients during the posttreatment period.
continued for another month. It was observed that 15 to 20 Another group, using a similar treatment regime, found that
mg (0.30-0.35 mg/kg) was the critical dose of prednisolone during a follow-up period of 5 years at least one third of the
to control a T1R after the initial period. The total duration of BL patients deteriorated after the prednisolone treatment.127
treatment was 4 to 9 months for BT patients, 4 to 14 months In Table 3, the result of the WHO treatment (1994-1995)
for BB patients, and 6 to 20 months for BL patients. The total is compared with the result of the treatment preferred at
follow-up period was 3 years.119 ALERT before 1974 and with those of the patient-tailored
When the results of the treatments are compared treatment in the period 1974 to 1978.119 It can be seen that
(Figure 13), the following can be seen: seven of the patients on WHO treatment had a higher VMT
deficit 9 to 12 months after treatment than before treatment.
1. During 1968 to 1974, there was no improvement in These results were better than those obtained with the short 1
the average value of VMT during the first half year, to 2 months treatment with prednisolone before 1974 at
though there was a gradual improvement thereafter. This ALERT but fell far short of those obtained by the
could be explained by assuming that the reaction settled longer-duration patient-tailored one. This small study
after a 4 to 9 months, the natural course during anti- found that at least half of the patients in T1R would benefit
leprosy treatment.121 from prolonged prednisolone treatment.
2. During 1974 to 1978 (Figure 13), there was a steady Based on the before mentioned studies,119,127 it was
improvement from the start of prednisolone treatment, unlikely that a short treatment could be effective in the long
the improvement continuing during the whole 3-year run; therefore, patients who had been treated with the
follow-up period. The average duration of treatment WHO-advised regimen and had been followed up with VMT
was 6 to 9 months, which is slightly longer than the were reassessed 3 to 8 months after prednisolone was stopped
treatment period described by some researchers117; (Figure 14).128 Data for 16 evaluable patients are shown in
however, they had studied BT patients. Figure 14. The graph in Figure 14 shows that although the
VMT deficit improved markedly during the prednisolone
It was clear that, in the field, individually tailored treatment in 15 of the 16 patients, 9 of them deteriorated
antireaction treatment was not feasible; therefore, fixed and subsequently to values not much different from the pretreat-
semi-fixed schedules were developed and implemented.122–124 ment values. The average result in VMT deficit before and 6
The results, in general, were good, although no long-term months after treatment was about the same. It is, therefore, not
follow-up was performed at that time. surprising that WHO for some time concluded that steroid
treatment resulted only in side effects and had no benefit.
The longer treatment durations are in accordance with the
experience of Rose and Waters129 and with reported data on
the length of T1R by Li Huan-Ying.121 The findings were
not revoked by other studies and analyses.4,109,129,130,131 A
large randomized controlled trial132 comparing three steroid
regimens in T1R also supported a longer duration, because it
found a significantly better outcome for a 20-week regimen
compared with a 12-week regimen, with fewer recurrences
and a reduced total required steroid dose.

Table 3 Comparison of treatment results for the periods


1968-1974, 1974-1978, and 1994-1995
Alert Alert Who
Patients (N) 25 23 16
Period ’68-’74 ’74-’78 ’94-‘95
Start or after 1 month 8 19 8
After 3 months 6 4 1
Fig. 13 Improvement in VMT's, vertical axis summation of After 6-12 months 11 0 7
VMT’s of both Abductor digiti minimi muscles and both the ALERT, Africa Leprosy and Rehabilitation Training Centre; WHO,
Abductor pollicis brevis muscles. Comparison of the treatment results World Health Organization.
between the period ’69-’73 and ’74-’78 over a 3 years period.
Leprosy type 1 reaction 47

Table 4 Time at which maximum nerve damage was observed


Paucibacillary Multibacillary
Dosage Time Dosage Time
40 mg 2 weeks 30 mg 1 month
Severity in arbitrary numbers

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

months; thereafter, it can be tapered off further under careful


observation of the nerve function (Table 4).
VMT and graded sensory testing are extremely useful
instruments for this. In patients with a contraindication for
the use of steroids, cyclosporine may be considered.135,136
Cyclosporine is an effective immunosuppressive agent, but it
has less antiedematous properties and especially in the first
Before starting After 3 months 6 months after
week it is less effective than steroids. The same applies for
azathioprine.137 With biologics, though effective in T1R (per
Prednisolone Prednisolone stopping WHO anecdotal reports), there is very little experience.
Steroid treatent A T1R regularly occurs after discontinuation of the
antimycobacterial treatment, probably due to the discontinuation
Fig. 14 WHO, World Health Organization. Improvement of VMT of dapsone, which has immune-modulating properties.138,139
during WHO advised treatment for T1R and the deterioration thereafter.
A reaction occurring after treatment should also be treated
with steroids. It is either an autoimmune reaction against
Recent data from Nepal (TRIPOD 1: “a 3-4 month antigenic determinants on the patients’ own tissue that are
prophylactic treatment with steroids in MB patents starting identical to those of M leprae or a reaction against remnant
on MDT”) report that a 3- to 4-month treatment schedule M leprae antigens.
does prevent nerve function impairment (NFI) at 4 and 6 It is advisable to check for parasites (worms) infections
months, but the effect is not sustained at 12 months.133 Based before steroid treatment is started; however, this should not
on all these data, it is likely that the 20-week regimen is too delay the treatment. When steroids are not effective in
short and should be extended again in the future. At this improving nerve function in the acute phase of T1R,
moment, two double-blind randomized controlled trials are mechanical nerve compression probably persists, and a
being conducted in Asia (TENLEP), the first to establish nerve release operation should be considered.102,104,140
whether prednisolone treatment of 32 weeks duration is more
effective than 20 weeks in restoring nerve function in leprosy
patients with clinical NFI (clinical trial), the second to Acknowledgments
determine whether prednisolone treatment of early subclinical
NFI can prevent clinical NFI (subclinical trial).134
Dr. Salvatore Noto and Dr. Pieter Schreuder provided
valuable suggestions.

Final recommendation: Back to the 1980s


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