Keywords:
Leprosy - botulinum toxins
Palavras-chave:
Hanseníase - toxinas botulínicas
Leprosy is a chronic granulomatous disease caused by Mycobacterium leprae, a bacterium with predilection for skin cells and peripheral nerve tissue. Thus,
it causes skin and neurological manifestations as well as inflammatory reactions with
consequent sensory and motor changes[1].
M. leprae has tropism for peripheral nervous system, infecting Schwann cells and occasionally
endothelium. Microscopic lesions' alterations include degeneration of Schwann cells,
loss of myelin, axonal retraction, periaxonal fibrosis and a variable amount of immunopathological
responses that result in progressive impairment of nerve fibers[2],[3],[4],[5].
There are two most common causes of pain in leprosy patients: leprosy reactions (LR),
which involve acute, inflammatory episodes of neuritis; and chronic pain resulting
from neuropathic damage. LR neuritis treatment involves anti-inflammatory drugs, like
prednisone; whereas neuropathic pain (NP) may be managed with prednisone or dexametasone
for type I reactions and thalidomide for type II reactions[6]. Tricyclic antidepressants (particularly amitriptyline), serotonin-norepinephrine
reuptake inhibitors (particularly duloxetine), pregabalin, gabapentin, tramadol, strong
opioids and botulinum toxin A (BoNT-A) are treatment options for NP[7].
The presence of neural damage sequelae is remarkable amongst leprosy patients. Many
studies have shown that NP is one leprosy's major sequelae, found in over 70% of patients.
Other prevalence factor of NP is the presence of LR, mainly type II reactions. In
addition, even the full therapy was unable to treat NP, which affects patients' quality
of life and mental health moderately to intensely[8],[9],[10].
Overt neuritis is statistically associated with evolution in the leprosy degree of
disability[11]. It is stated as pain presence, spontaneous or by palpation, of a peripheral nerve
trunk, with or without impaired function, possibly leading to nerve damage, alterations
in free nerve endings and nerve trunks, that may cause loss of sensation, paresis,
plegias and muscular atrophies, which if not diagnosed and properly treated, may progress
to permanent physical disabilities[12].
In Brazil, leprosy is the most common underlying cause for peripheral neuropathy treatment,
and despite being an age-old disease, it still challenges humanity. Moreover, a significant
portion of patients, even after discharge from specific medication, suffers from the
sequelae of nerve damage caused by the disease[13].
Brazil's leprosy epidemiology bulletins (2018) indicate that there is still high prevalence
of such disease in the country, which is therefore recognized as an endemic zone,
with medium detection rate of 14.97 new cases per 100,000 inhabitants[14]. Thus, the association of early diagnosis and appropriate treatment has vital significance
for the affected population's quality of life improvement[15].
These observations denote the need for new studies, including commonly used drugs
for neuropathic pain treatment; also, there is no description of botulinum toxin type
A for chronic neuropathic pain control in leprosy. Thus, the aim of this study was
to analyze the effectiveness of botulinum toxin type A (BoNT-A) in chronic neuropathic
pain in refractory leprous patient treatment, as well as to evaluate and compare the
quality of life of patients before and after using such medication.
METHODS
This was a self-control open-label study of therapeutic intervention in patients with
chronic neuropathic pain after leprosy refractory treatment[6]. Botulinum toxin (neuromuscular junction blocker) was used for treatment. The study
groups were assessed and monitored for a period of eight weeks (two months). Patients
were evaluated on days 0, 10 and 60.
Patients invited to participate in the study were selected from the referral center
for the care of leprosy in the city of Belém, Pará, Brazil, represented by outpatient
clinics of the Tropical Medicine Center (TMC) and the Health Center School - Marco
(CSEM). Overall, 163 patients with leprosy and pain were assessed, of whom, only 41
met the minimum criteria to be included in the study (age above 15 years and chronic
neuropathic pain). However, 20 of these patients showed other conditions such as diabetes,
HIV, and chronic alcoholism and were therefore excluded. The remaining sample comprised
21 patients with chronic neuropathic pain leprosy, of which only 15 agreed to participate.
Until study end, the 15 patients treated or not with multidrug therapy (MDT) presented
alteration of dermatologic/neurologic examination, like sensory or motor deficit.
The NP was characterized by Douler Neuropathique en 4 Questions (DN4) above 4 in 10, visual analog scale (VAS) above 5 and were submitted to treatment
for neuropathic pain with drugs proposed by the Brazilian Ministry of Health[6] with no improvement in the clinical condition. Quality of Life was assessed and
measured through World Health Organization Quality of Life Brief Questionaire (WHOQOL-Bref)
at the beginning and end of study.
Also, Chen et al.[16] criteria were included in this study, which establishes chronic neuropathic pain
leprosy as a painful condition of at least two years after treatment with MDT or after
three months with continuous or uninterrupted pain, associated or not with leprosy
reaction, with no evidence to suggest other causes, such as infected ulcers.
Botox® BTX-A 100 U administration followed Patil et. al.[17] recommendations (Dilution in 2 mL of 0.9% saline solution, where each 0.1 cc match
5U of BoNT-A). Application followed dermatomes or affected nerve endings, determined
by clinical and neurophysiological examination and marked with a color pen[17] ([Figure 1]).
Figure 1 Application points of botulinum toxin.
The study received approval of the insitutions' Ethics Committee.
RESULTS
All 15 participants met the inclusion criteria and thus were submitted to treatment
with BoNT-A.
Patients had longstanding chronic pain which lasted 1 to 20 years (mean time = 4.4
years), with no significant difference in pain time (p = 0.4562). About pain site,
there was significant incidence of commitment of upper and lower limbs concomitantly
(46.7%, p = 0.0457) ([Table]).
Table
Sociodemographic and clinical characteristics of patients with chronic neuropathic
pain.
|
Variables
|
Frequency
|
%
|
p X2
|
|
Sex
|
|
Female
|
6
|
40
|
0.0486
|
|
Male*
|
9
|
60
|
|
Age group (years)
|
|
< 30
|
3
|
3.8
|
0.0402
|
|
30 to 39
|
4
|
5.0
|
|
40 to 49*
|
6
|
7.5
|
|
≥ 50
|
2
|
2.5
|
|
Mean-female
|
36.2 (SD 6.7)
|
|
|
|
Mean-male
|
45.9 (SD 14.3)
|
|
|
|
Mean-general
|
42 (SD 13)
|
|
|
|
Madrid classification
|
|
Dimorphic*
|
11
|
73.3
|
< 0.0001
|
|
Virchow
|
2
|
13.3
|
|
Tuberculoid
|
1
|
6.7
|
|
Pure neural
|
1
|
6.7
|
|
WHO classification
|
|
MB*
|
13
|
86.7
|
< 0.0001
|
|
PB
|
2
|
13.3
|
|
Reactions
|
|
Type I
|
8
|
53.5
|
0.3147
|
|
Type II
|
2
|
13.3
|
|
Absent
|
5
|
33.3
|
|
Bacilloscopy (n = 14)
|
|
Positive*
|
10
|
66.7
|
0.0291
|
|
Negative
|
4
|
26.7
|
|
Incapacity
|
|
Absent
|
2
|
13.3
|
0.0098
|
|
Present
|
13
|
86.7
|
We observed a significant increase (p = 0.0010) of strength after application of the
toxin. This increase occurred from the tenth day after the use of medication (p =
0.0361), reaching its peak on the sixtieth day of evaluation ([Figure 2]).
Figure 2 Oxford Strength Scale degree.
Pain intensity evaluation (VAS) showed significant reduction (p = 0.0057) from days
10 to 60. The therapy reduced pain levels quickly in the first week after BoNT-A application
and stabilized on the remaining days until study end ([Figure 3]).
Figure 3 Visual Analogue Scale for pain
We found an increase in all domains of the QoL scale, with the Quality of Life (p = 0.0147 *) and Physical (p = 0.0052) domains significantly different between these periods, since these domains
reported better quality of life after intervention. The comparison between domains
showed significant difference only before treatment (p = 0.0134) ([Figure 4]).
Figure 4 World Health Organization Quality of Life Brief Questionaire (WHOQOL -Bref).
In relation to adverse effects, five patients complained of headache, tingling, nausea,
fever, drowsiness, left foot edema and pain in the right lower limb on the first week
after application. However, such complaints were not known as adverse effects of medication.
DISCUSSION
Pimentel[12] evaluated 103 patients with multibacillary leprosy, highlighting peripheral nerve
involvement at diagnosis, disability degree before treatment and occurrence of neuritis
episodes during and after multidrug therapy, which led to discovery that the ulnar
nerve is the main damaged nerve. Similar results were found in this study, with 12
cases (80%) of ulnar and tibial, 10 cases (66.67%) of radial and nine cases (60%)
of fibular nerve damage[2].
Chen et al.[16] described neuropathic pain prevalence of 126 patients within a 275-leprosy patient's
sample (45.8%), exposing this disorder severity. In addition, 109 patients (86.5%)
referred that pain had impact over Quality of Life, being that 13 (10.3%) patients
referred mild, 45 (35.7%) referred moderate and 51 (40.5%) referred severe interference
of pain in Quality of Life. Actual literature also confirms sociodemographic aspects
of the leprous population, finding similar results to our study[16].
In all cases, there was a reduction of pain since five days after application. In
one of the reported cases, there was significant reduction of pain that lasted for
eight weeks. Chen and Chuang[18] made serial applications with three-month intervals and thus maintained the pain
score near zero in a group of patients with post-herpetic neuralgia. Our main results
showed that a single subcutaneous application of BoNT-A induces a long-term analgesic
effect on neuropathic pain. The effects found had quantified measures, particularly
the evaluation of VAS, as a way of pain assessment. We observed reduction in the intensity
of allodynia in the affected nerve territory from the first week lasting until the
eighth[18].
Neuropathic symptoms and some quality of life questions improved in our patients.
These characteristics indicate that BoNT-A has selective effects on neuropathic pain
likely indicating new mechanisms for analgesia. Similar results can be seen in Park's
studies (2017) regarding whether the occurrence of pain is spontaneous or not, its
intensity, its perception mechanism, neuropathic symptoms and quality of life of these
patients at weeks 0, 4, 12 and 24 after application BoNT-A[19].
Xiao et al.[20] reported sixty cases of post-herpetic neuralgia treated with BoNT-A (Botox®) in dilution 5u/mL, and applied 5 IU per point, for a total of 100 IU. The severity
of pain was assessed by VAS, with a significant reduction from the seventh day and
maintained until three months. In relapse, pain was considered less severe and tolerable
by patients[20].
Other studies corroborate the usefulness of botulinum toxin A in peripheral neuropathic
pain treatment[21],[22]. Therefore, the specific study in the treatment of patients with leprosy is of great
importance.
In conclusion, botulinum toxin displayed the action described in diseases that occur
with excessive muscle contraction, as facial spasm, spasticity, in addition to its
indication in some pain syndromes, like migraine and painful neuropathies.
The study proposed the therapeutic use of botulinum toxin in leprosy patients who
evolved with neuropathic pain. The toxin had good tolerance, as the only notable side
effect was transient mild to moderate pain during injections in many patients, especially
when applied to extremities and affected nerve territories.
With only a single subcutaneous injection of BoNT-A, direct analgesic effects over
the long term were promoted in patients with chronic neuropathic pain leprosy associated
with allodynia, suggesting that the analgesia observed may be caused by a local peripheral
effect of BoNT-A on nociceptive nerve endings, although subsequent central effects
are possible. The study suggests that BoNT-A is a good option for cases of chronic
neuropathic pain leprosy; however, further studies are needed to confirm these results.
