Keywords: Leprosy - Decompression, Surgical - Neuralgia - Peripheral Nerves
Palavras-chave: Hanseníase - Descompressão Cirúrgica - Neuralgia - Nervos Periféricos
INTRODUCTION
Leprosy is among the main causes of tractable peripheral neuropathy in the world[1 ], with an estimated occurrence of more than 15/100.000 inhabitants in Brazil[2 ]. Invasion of Mycobacterium leprae into a nerve leads to either a direct or indirect inflammatory process, termed neuritis,
clinically defined when there is some impairment of neural function (sensory and /
or motor), with or without pain (silent neuritis)[3 ]. The neural impairment is caused not only by the infection, but also by the immune
reactions, which can lead to the main sequelae and deformities in this neuropathy,
causing serious physical, social, and psychological disorders[4 ]. The neural damage due to leprosy may occur before and during the course of the
disease, even after standard treatment with multidrug therapy (MDT)[5 ].
The treatment of choice for neuritis is clinical and consists of steroid therapy
and limb immobilization[5 ]. The pain in leprosy neuritis can be nociceptive due to the inflammation process
that occurs during episodes of immune system-mediated reactions, or it can also be
neuropathic, considering that leprosy may affect the somatosensory system[6 ]. The prevalence of neuropathic pain in individuals with leprosy is still not well-documented
and probably underestimated[7 ].
Peripheral neural surgical decompression (PNSD) is used as a complementary therapy
to clinical neuritis treatment with the objective of preserving neural function and
is not recommended in cases without previous clinical treatment[8 ]. In some randomized controlled trials, the combination of surgery and medical treatment
did not show additional benefit in relation to medical treatment alone[9 ],[10 ]. However, after a Cochrane’s review of the subject, it was concluded that the results
of these studies were not sufficient to evaluate the effects of the surgery, and that
new studies with larger populations and with long-term follow-ups were necessary to
evaluate the possible favorable predictive factors for decompressive surgery[8 ],[11 ]. The epidemiological and clinical profiles of these patients make them inappropriate
for randomized controlled trials; in addition, non-randomized studies that evaluated
the effects of PNSD showed a tendency toward pain relief[3 ],[12 ]
-
[14 ].
This study aimed to evaluate the long-term effectiveness (at least one year) of surgical
treatment, using assessments of motor and sensory function, degree of functional disability,
intensity of pain, prednisone dose, and satisfaction with surgery.
METHODS
Patients and data collection
This cross-sectional study selected 90 leprosy patients aged 18 to 80 years and both
genders who underwent PNSD with at least one postoperative year, from the National
Reference Center for Sanitary Dermatology and Leprosy from January 2010 to May 2014.
This study was approved by the Committee of Ethics in Research from the Federal University
of Uberlândia (CAE: 235203146.0000.5152). Written informed consent was obtained from
all participants.
The PNSD was recommended only in cases where the clinical treatment of neuritis leprosy
was ineffective. The following inclusion criteria were adopted for all patients in
the study: presence of nerve abscess, neuritis that does not respond to standardized
clinical treatment within 4 weeks, with worsening dermatoneurological evaluation,
cases of reentrant neuritis (when a new clinical impairment occurs in the attempt
to withdraw or reduce the dose of corticosteroids), tibial neuritis with or without
the presence of a plantar ulcer, as it could be silent and does not always respond
well to corticosteroids and in cases of neuritis associated with other comorbidities
that contraindicate the use of corticosteroids.
The clinical treatment of neuritis consisted of maintaining the multidrug therapy
(MDT) for patients who were still undergoing treatment against leprosy, immobilization
of the affected limb, in a combination with the use of prednisone at a dose of 1 mg/kg
daily for cases of type 1 and 2 reactions and use of thalidomide only for type 2 reactions,
and with actions to prevent disabilities, such as motor physical therapy and periodic
evaluation with an occupational therapist.
Patients with chronic alcoholism, diabetes mellitus, thyroid disease, hereditary neuropathy,
human immunodeficiency virus, autoimmune diseases, or previous injuries were excluded.
Epidemiological, socioeconomic, and clinical data were examined. The patients were
classified as tuberculoid (TT), borderline-tuberculoid (BT), borderline-borderline
(BB), borderline-lepromatous (BL), and lepromatous leprosy (LL)[15 ]. Data collected in the late post-operative (LPO, ≥1 year) evaluation were compared
with those of the preoperative (PrO) and 180-day postoperative (PO180) periods, which
was recorded in the medical records.
The perceptions of activity limitation by the patients were evaluated using the Screening
of Activity Limitation and Safety Awareness (SALSA scale) at the LPO, which consists
of a questionnaire with 20 items divided into five areas involving the eyes, hands
(skills and work), feet (mobility), and self-care. The results are classified into
several groups: (1) 10 - 24 (no limitation of activities); (2) 25 - 39 (mild limitations);
(3) 40 - 49 (moderate limitations); (4) 50 - 59 (severe limitations); and (5) 60 -
80 (very severe limitations)[16 ].
Neurological evaluation
All the subjects were submitted to a simplified neurological assessment protocol by
the institution’s physiotherapy team that is standardized by the Ministry of Health
in Brazil and used in all reference centers for leprosy.
Sensorial evaluation of each nerve was performed using the six Semmes-Weinstein filaments,
which exert forces of 0.05, 0.2, 2, 4, 10, and 300 g on the skin. In the presence
of a negative response to the lightest monofilament (0.05 g), the test was carried
out using monofilaments of increasing thickness, i.e. 0.2, 2, 4, 10, and 300 g, until
a positive response was obtained. In the upper limbs, three points were evaluated
for the median (points 1, 2, and 3) and ulnar (points 4, 5, and 6) nerves. In the
lower limb, nine points were evaluated for the tibial nerve (points 1-9) and one point
for the common fibular nerve (point 10). Each of these points received a score that
varied from 0 to 5, with a maximum score of 15 for the median and ulnar nerves, 45
for the tibial nerve and 5 for the common fibular nerve ([Figure 1 ])[17 ].
Figure 1 (A) Semmes-Weinstein esthesiometer with six nylon monofilaments of different diameters
and the scores attributed to each monofilament: 0.05 g (green); 0.2 g (blue), 2 g
(purple), 4 g (red), 10 g (orange) and 300 g (pink). (B) In the upper limbs, three
points were evaluated for the median (points 1, 2 and 3) and ulnar (points 4, 5 and
6) nerves. In the lower limb, nine points were evaluated for the tibial nerve (points
1-9) and one point for common fibular nerve (point 10). Each of these points received
a score that varied from 0 to 5, with a maximum score of 15 for median and ulnar nerves,
45 for the tibial nerve, and 5 for the common fibular nerve.
In order to assess motor function, the following muscles were evaluated in the upper
limbs: abductor pollicis brevis and lumbricals (first and second) for the median nerve,
first dorsal interosseous, abductor digiti minimi, and lumbricals (third and fourth)
for the ulnar nerve. In the lower limbs, only the muscles innervated by the deep fibular
nerve were assessed (tibial anterior, extensor digitorum longus, and extensor hallucis
longus). According to functional condition, scores that ranged from 0 to 5 were assigned
on each evaluated muscle as the Medical Research Council scale, with a maximum score
of 10 for median nerve, 15 for ulnar nerve, and 15 for common fibular nerve ([Chart 1 ])[17 ].
Chart 1
Medical Research Council (MRC) muscle grading scale with scores for assessment of
motor strength.
Grade
Description
Score
5
Full range of movement at the joint with normal resistance
5
4
Full range of movement but with less resistance
4
3
Full range of movement with no resistance
3
2
Perceptible contration of muscles not resulting in joint moviments
2
1
1
0
Complete paralysis
0
The level of functional disability evaluates the neural function integrity and the
degree of physical disability, through voluntary muscle testing and sensorial evaluation
of the hands and feet. When there is no neural impairment, patients are classified
as disability grade zero (DG0) and when there is only sensorial impairment they are
classified as disability grade 1 (DG1). Regarding disability grade 2 (DG2), there
are visible deficiencies, such as clawed fingers, bone resorption, muscle atrophy,
contractures, and wounds[17 ].
Degree of intensity of postoperative pain of each nerve was assessed by using the
Visual Analog Scale for Pain (VAS) at the PrO and LPO[18 ] evaluations. The prevalence of neuropathic pain was evaluated only at the LPO evaluation
by applying the questionnaire Douleur Neuropathique en 4 Questions (DN4), a universal instrument validated for Portuguese[19 ].
Surgical technique
Patients undergoing surgery followed the referral protocol and surgical techniques
recommended by the Ministry of Health[20 ]. The ulnar nerve was approached through the medial face of the elbow with anterior
transposition. For the median nerve, the carpal tunnel canal was opened, and adhesions
were released along the nerve. For the tibial nerve, the incision was below the medial
malleolus with an opening made in the fibrous tunnel for neural decompression. The
common fibular nerve was approached through the opening of the fibro-osseous canal
in the fibular head with decompression of superficial and deep branches.
Considering that leprosy neuropathy manifests as an asymmetrical multiple mononeuropathy
and that the risk of recurrence and involvement of other neural trunks in the ipsilateral
limb is high during reaction episodes, neural decompression surgery is always performed
in a combined manner: median and ulnar nerves when operating on the upper limbs, and
when operating on the lower limbs, the fibular and the tibial nerves are decompressed
in the same surgical procedure. Decompression is always performed on the most affected
limb and never simultaneously, considering the need for limb immobilization and the
need for early rehabilitation.
Statistical analysis
Non-parametric tests were used, and normality tests for quantitative variables indicated
that these did not follow a normal distribution (p < 0.05). Therefore, McNemar’s test
was used for comparisons between PrO and LPO for qualitative data and Wilcoxon’s test
for quantitative data. The comparisons among PrO, PO180, and LPO was also done with
Friedman’s test. All the tests were done with software SPSS (v20), and a level of
significance of 5% was accepted.
RESULTS
Clinical and socioeconomic characteristics
The socioeconomic variables, clinical classification, and operational classification
of patients are described in [Table 1 ]. Among patients included in this study, 78.9% (71/90) were multibacillary (MB) and
BT clinical form was the most prevalent (38.9%; 35/90). Regarding the time of surgical
referral, 56.6% (51/90) of patients were submitted to PNSD during treatment with MDT
and 43.3% (39/90), after the end of treatment. In this group, the average time between
the end of treatment and surgery was 33.27 months (±27.68) (median=19 months).
Table 1
Demographic data, including socio-economic and clinical variables.
Variable
N=90
%
Gender
Female
31
34.4
Male
59
65.6
Age (years)
23 a 34
11
12.2
35 a 46
33
36.7
47 a 58
28
31.1
59 a 70
14
15.6
>70
4
4.4
Occupational status
Active
28
31.1
Retired
46
51.1
Sick leave
16
17.8
Type of Retirement
Disability
32
69.5
Age
14
30.4
Clinical classification
Lepromatous
10
11.1
Borderline-lepromatous
19
21.1
Borderline-borderline
15
16.7
Borderline-tuberculoid
35
38.9
Tuberculoid
11
12.2
N: number of cases; %: percentage of cases.
A total of 246 nerves (123 surgical procedures) were operated on 90 patients, with
an average of 2.7 nerves per patient. There was a greater recommendation of surgical
procedure on the nerves of the upper limbs, with combined median and ulnar decompression
in 57.6% (142/246) of the cases. Around 77% (69/90) of individuals were operated on
only one limb (two nerves), 14.4% (13/90) were operated on two limbs (four nerves),
4.4% (4/90) were operated on three limbs (six nerves), and 4.4% (4/90) were operated
on four limbs (eight nerves).
Isolated ulnar neuritis was responsible for surgical referral in 26.0% (32/123) of
operated cases, followed by isolated tibial neuritis in 23.6% (29/123). The remaining
cases had more than a single altered nerve at the time of surgical referral. Only
2.2% of individuals (2/90) presented complications in the immediate postoperative
period, requiring a new surgical approach. After PNSD, 14.4% (13/90) presented at
least one immune reaction episode.
Patient perception
Regarding the patients' perception of the surgery, 80% (72/90) of individuals reported
that the results reached their expectations; 16.7% (15/90) expected better results
with the surgery, and 3.3% (3/90) reported that the surgery did not meet their expectations
and the results were worse than expected.
In assessing the limitations of functional capacity according to the SALSA scale,
10% (9/90) of individuals did not have limitations in activity performance, 51.2%
(46/90) had mild limitations, 34.4% (31/90) had moderate limitations, 3.3% (3/90)
were severe, and 1.1% (1/90) presented very severe limitations.
Pain assessment
In PrO, 74.4% (67/90) of individuals presented pain, and at the LPO, 55.5% (50/90).
At this time, 74% (37/50) of these patients presented characteristics of neuropathic
pain according to DN4. When the average intensity of pain by VAS was compared for
the PrO and the LPO periods, a significant difference was noticed, indicating a significant
reduction in pain intensity (p<0.001) ([Figure 2 ]).
Figure 2 *p<0.001. Average pain intensity (VAS) in the preoperative (PrO) and late postoperative
periods (LPO) in each of the operated nerves. There was a reduction in pain intensity
in all operated nerves.
Prednisone dosage
At the time of surgical referral, 43.3% (39/90) of patients were using high-dose prednisone
(1mg/kg daily) for more than 6 months and 52.2% (47/90) reported some adverse effect
of the chronic use of corticosteroids. Only 15.5% (14/90) of the individuals maintained
the use of prednisone in the POT. The mean dose of prednisone used was 39.6 mg (±3.0)
in PrO, 16.3 mg (±5.2) in PO180 and 1.7 mg (±0.8) in LPO. The reduction in prednisone
dose was statistically significant when the PrO dose was compared to PO180 and LPO
(p<0.001) ([Figure 3 ]).
Figure 3 The mean dose of prednisone in mg showed a significant reduction (p<0.01) between
the preoperative period (PrO), the postoperative period of 180 days (PO180) and the
late postoperative period (LPO) (p<0.001).
Neurological assessment and incapacity level
There was a significant increase in the motor score in all of the nerves that underwent
surgery, except for the left fibular nerve ([Table 2 ]), when comparing the three study periods (PrO, PO180, and LPO).
When the sensory score of the nerves that underwent surgery were compared during the
three study periods (PrO, PO180, and LPO), an improvement in the left right fibular
and tibial nerves was noted comparing the PrO with PO180, but no improvement was found
when comparing only the PrO with LPO ([Table 2 ]). However, regarding the ulnar nerves, a significant improvement (p <0.05) was observed
when comparing the PrO with PO180 and also with LPO.
Table 2
Means, standards deviation and comparison of the sensory and motor scores of the operated
nerves in the PrO, PO180, and LPO periods.
Sensory Score
PrO
PO180
Wilcoxon*
LPO
Wilcoxon**
Friedman
Nerve
Mean ±SD
Mean ±SD
p valor
Mean ±SD
p valor
p valor
Ulnar L
6.9 ± 5.1
8.0 ± 6.0
0.123
8.58 ± 5.0
0.026*
0.371
Median L
10.4 ± 5.2
11.6 ± 4.7
0.028*
11.5 ± 4.5
0.088
0.234
Ulnar R
5.6 ± 5.0
7.0 ± 5.3
0.025*
7.4 ± 5.5
0.048*
0.422
Median R
10.4 ± 5.7
11.5 ± 4.6
0.081
11.4 ± 5.2
0.106
0.192
Tibial R
10.2 ± 10.6
14.6 ± 12.8
0.004*
14.2 ± 14.3
0.080
0.036*
Fibular R
1.3 ± 1.9
1.8 ± 2.1
0.032*
1.5 ± 1.8
0.262
0.049*
Tibial L
8.0 ± 11.1
11.1 ± 13.9
0.041*
9.0 ± 12.5
0.477
0.048*
Fibular L
1.04 ± 2.0
1.46 ± 2.24
0.093
1.0 ± 1.5
0.778
0.340
Motor Score
PrO
PO180
Wilcoxon*
LPO
Wilcoxon**
Friedman
Nerve
Mean ±SD
Mean ±SD
p valor
Mean ±SD
p valor
p valor
Ulnar L
8.3 ± 3.7
9.9 ± 3.9
0.001*
11.4 ± 3.5
0.000*
0.001*
Median L
7.5 ± 2.0
8.4 ± 1.8
0.003
8.8 ± 1.6
0.000*
0.001*
Ulnar R
7.3 ± 3.2
8.7 ± 3.9
0.006*
9.4 ± 3.6
0.000*
0.001*
Median R
6.5 ± 2.3
7.6 ± 2.1
0.018*
8.7 ± 1.5
0.000*
0.001*
Fibular L
9.7 ± 5.8
10.1 ± 5.4
0.313
10.2 ± 5.2
0.497
0.274
Fibular R
10.5 ± 5.0
12.5 ± 4.0
0.024*
13.2 ± 3.6
0.007*
0.010*
PrO: preoperative period; PO180: 180 days postoperative period; LPO: late postoperative
period; L: Left; R: right; SD: standard deviation; *Wilcoxon test used to compare
PrO with PO180; **Wilcoxon test was used to compare PrO with LPO; Friedman test was
used to compare the three periods; *Values of p<0.05 indicate a statistically significant
correlation.
Considering the evaluation of the DG in the PrO, 47.3% (17/36) of left upper limbs,
57.1% (20/35) of right upper limbs, 62.9% (17/27) of left lower limbs, and 52.2% (13/25)
of right lower limbs presented DG2. During the LPO period, there was a reduction in
the DG in all assessed limbs, but with significance only in the right lower limbs
(p=0.001).
DISCUSSION
The sample had a preponderance of men, mostly in the economically active age range,
which corresponded with results from previous studies[3 ],[21 ]. According to the operational classification, there was a higher number of multibacillary
and borderline-tuberculoid in clinically diagnosed patients, considering that this
is an endemic area[22 ]. In the borderline forms, many nerve branches are affected, and the deformities
due to neural damage are the worst[23 ]. The ulnar nerve is the most frequently affected in leprosy[24 ],[25 ], which justifies the high incidence of surgery in the upper limbs in this study.
Between 15 and 65% of leprosy patients presented irreversible neural damage during
the course of the disease, which occurs principally during the reactional episodes[26 ]. In our study, most patients underwent PNSD due to the lack of response to medical
treatment during reactional episodes, justifying the high incidence of adverse effects
related to chronic use of corticosteroids. In addition, the presence of deformities
and neural sequelae already at the time of PNSD, reinforces not only the late referral
for surgical treatment, but also the difficulty of referring these patients to centers
that perform this procedure.
It is important to emphasize that in some cases, even after PNSD, patients can still
present new reaction episodes, reinforcing the need for a strict clinical monitoring
in the postoperative period. Besides that, a considerable proportion of the patients
included in this study underwent the surgical procedure many months after the end
of treatment, corroborating the presence of permanent sequelae and less chance of
recovery.
Even considering that not all patients had improved sensory-motor function, the stabilization
of the process, without worsening symptoms, was one of the reasons for which the patient’s
expectations were met. When confronting these results with those of the SALSA scale,
it was observed that this satisfaction could also be explained due to absence of limitations
or mild limitations in the performance of daily life activities found in almost 60%
of patients during the LPO period[16 ].
Another factor that contributed to most patients considering the surgery satisfactory
was the reduction in pain intensity. In the individuals evaluated, a sharp drop in
pain intensity was found when the PrO pain was compared to LPO pain, similar to results
of other studies[3 ],[12 ]
-
[14 ]. However, a considerable proportion of patients presented neuropathic pain during
the LPO period, reinforcing the need to optimize pain treatment in these patients,
including differentiating between chronic pain and new reaction episodes.
There are various pathogenic mechanisms involved in the origin of neuropathic pain
in leprosy, such as acute neural inflammation and trapped nerves, leading to activation
of the nerve fibers that innervate the neural sheaths (nervi nervorum )[27 ]. The development of chronic neuropathic pain in patients whose infections were treated
successfully contributes to an unsatisfactory quality of life[28 ]. In previous studies, the incidence of neuropathic pain in patients who were undergoing
clinical treatment was 56.1%, and most patients reported severe pain that interfered
with their daily activities[29 ]. In another study, the incidence of pain was 29%, of which half of the patients
presented moderate pain[30 ]. These studies show that neuropathic pain is an important complication of leprosy
neuritis without considering the type of treatment and certainly needs to be addressed
in this group of patients.
Reduction of postoperative prednisone dose in both analyzed periods suggests that
corticosteroid was used in high doses probably because the medication could not reach
the swollen and ischemic nerves, and that the present symptoms would be related to
the external compression of the nerves[3 ]. The reduction in prednisone dose would lead to a lower incidence of adverse reactions,
which is desirable in medical treatment, and thus decreasing the morbidity and mortality
related to corticosteroid use[31 ]
-
[32 ].
When assessing sensory function during the LPO period, there was no substantial improvement
of scores, especially in the lower limbs, reinforcing the problem of late surgical
referral, when most patients already had a marked sensory impairment in the assessment
of disability degree, which can also indicate an irreversible loss of sensations at
the time of surgery referral[33 ]. Neural impairment in leprosy is predominantly sensorial in the early stages of
the disease, and these nerve fibers are injured earlier during the course of leprosy
in relation to motors fibers[34 ],[35 ]. This data reinforces the importance of timely treatment during reaction episodes
and the need to refer patients to evaluation of surgical treatment at earlier stages.
In relation to motor function, there was an improvement in all the nerves that underwent
surgery[36 ],[37 ], except for the left fibular, which did not present the same level of recovery.
We can conclude that the motor result was favorable, in contrast to sensory function,
reinforcing that even with late referral, the surgery obtained satisfactory results
and can contribute to a functional improvement of patients.
The data obtained in this study reinforce the importance of monitoring patients affected
by leprosy, not only during treatment, but also after discharge. Among multibacillary
patients, who are the majority of new cases in Brazil, the frequency of DG2 is still
high, between 33 and 56%[38 ]. The DG on admission to the health service is considered a predictor of disability
progress and reinforces the need for an early diagnosis to prevent neural damage[39 ]. In this study, a large number of individuals were multibacillary, and more than
half already presented DG2 in one of the extremities when there was recommendation
for PNSD, which can justify a less than meaningful improvement in all nerves.
There is a lack of consensus about the exact moment for carrying out PNSD for treatment
of leprous neuritis, which has led the teams of the Reference Centers to refer patients
for this procedure only when there is the threat of irreversible motor neural damage.
The results of this study show that PNSD in leprosy is effective in the long-term,
especially in decreasing prevalence and the intensity of the pain. It also improves
motor function and reduces the dosage of corticosteroid, all of which are reflected
in the patients’ satisfaction with the surgery.
The pathogenesis of the peripheral nervous system involvement in leprosy is based
on two main concepts around which neural damage is better understood: the infection
of Schwann cells and the presence of perineural inflammation, resulting from different
mechanisms related to the interaction between M. leprae and the host. In reaction episodes, the bacillus causes peripheral neuropathy of
mainly inflammatory and immunological origin, comprising the action of antibodies,
cytotoxicity, and other mechanisms that can result in motor, sensory, and autonomic
impairment. However, neural involvement can also result from edema and local mechanical
processes, as the involvement of Schwann cells and the presence of neural thickening
can make neural fibers more susceptible to compressive effects and the edema of nerve
trunks, which can even lead to an ischemic impairment. Therefore, PNSD should be a
treatment option for cases of neuritis refractory for clinical treatment.
Considering that reaction episodes represent the main cause of disability in leprosy,
medical and surgical treatment of patients with leprosy neuritis should be optimized
in leprosy-endemic countries. This study performed a retrospective analysis and did
not evaluate new possibilities in the medical treatment of neuritis, such as the use
of endovenous corticosteroid for cases of greater severity, or the use of immunosuppressants
in individuals who are on a prolonged use of prednisone. The ideal study model to
observe the impact of the PNDS would be to assess whether there is a difference in
the evolution of groups that underwent the procedure or not, preferably by evaluators
who do not know which patients underwent the procedure.
This study reinforces the need for a review of the parameters used in the sensory-motor
assessment performed routinely at leprosy reference centers and adopted as part of
the PNSD referral criteria. In addition, the clinical heterogeneity of the patients
included in the study regarding the duration of the disease, the number and type of
reaction episodes, could influence the use of corticosteroids and also the physical
examination findings, therefore influencing the results obtained.
In relation to the PNSD, future studies should propose an earlier intervention in
individuals without sequelae and permanent deformities that could be guided not only
by clinical parameters, but also through electroneuromyography that could evidence
the presence of conduction block, temporal dispersion, and other objective neurophysiological
findings and by ultrasound of peripheral nerves that could more accurately locate
compression sites, making the assessment more objective and accurate.
