Evaluation of altered patterns of tactile sensation in the diagnosis and monitoring of leprosy using the Semmes-Weinstein monofilaments.

BACKGROUND: Leprosy neuropathy is the most common peripheral neuropathy of infectious etiology worldwide; it is characterized as asymmetric and focal multiple mononeuropathy. Semmes-Weinstein monofilament (SWM) test is a simple method to assess sensory nerve function. METHODS AND
FINDINGS: In this prospective cohort study, a dermatologist carried out hands and feet tactile sensation test with SWM in 107 multibacillary leprosy patients at diagnosis and in 76 patients at the end of treatment from 2016 to 2019. At diagnosis, 81/107 (75.7%) patients had some degree of functional disability, and 46 (43%) of them had altered SWM-test in the hands and 94 (87.9%) of them in the feet. After one year of multibacillary multidrug therapy, the disability decreasing to 44/76 patients (57.9%) and decreasing of the percentual of patients with altered SWM-test to 18% for the hands, and to 28.7% for the feet. At the end of treatment, the number of SMW-test points presented improvement in the hands of 22 (28.9%) patients, and in the feet of 47 (61.8%). In the hands, by SWM-test, only the radial nerve point demonstrated a significant asymmetry, while in the feet, the difference between the sum of altered SWM-test points showed significant asymmetry between both sides, highlighting the tibial nerve for the establishment of asymmetric leprosy neuropathy. In Spearman's correlation analysis, a positive correlation with statistical significance was observed between the number of hands and feet SWM altered points at diagnosis and the degree of disability at diagnosis (0.69) and at the end of the treatment (0.80).
CONCLUSION: The patterns of hands and feet tactile sensation at diagnosis and their consequent modifications with the anti-leprosy drugs define the bacterial etiology of neuropathy, an important tool for the clinical diagnosis and follow up of the disease, highlighting the tibial nerve findings, the most affected nerve among leprosy patients by SWM-test, with significant asymmetry and focality impairments.

Introduction

Among the neuropathies caused by bacteria, there are Lyme disease and leprosy [1]. While in the first, peripheral neuropathy is usually a late, mild, diffuse and “sock and glove” distribution, in leprosy, neural involvement is early and characterized as asymmetric and focal multiple mononeuropathy [2, 3]. The improvement of neurological symptoms in leprosy with antibacterial drugs is evidence of the infectious cause of neuropathy, and it should be valued as therapeutic evidence, mainly for patients with negative complementary laboratory tests.

In leprosy, the existing data on neurological manifestations and the predominance of sensory or motor involvement are often contradictory and the methodologies and objectives of the work are diverse. In a series of studies [4-12], leprosy neuropathy is predominantly sensitive, heat and pain sensitivities are the most compromised and, in general, it has an asymmetric pattern (multiple mononeuropathy).

If peripheral nerve changes are not identified, monitored and treated appropriately, the result is irreversible nerve damage, which can result in permanent deformity and disability [13]. Semmes-Weinstein monofilaments (SWM) are used to assess and monitor tactile sensation in specific territories of the nerve trunks of the hands and feet. The standard esthesiometer kit recommended by the Ministry of Health of Brazil is composed of six nylon monofilaments, 38 mm long and with different diameters, which exert a specific force that corresponds to weight variation from 0.07 to 300 gram-force (gf) [14].

Considering that the involvement of peripheral nerves is present in all clinical forms of leprosy, usually as an asymmetric peripheral neuropathy, predominantly sensitive [15], it is important to assess the patterns of hands and feet SWM-test at diagnosis, as well as their clinical-therapeutic follow-up in an objective way.

Our objectives were to evaluate patterns of SWM-test changes in the hands and feet of leprosy patients at diagnosis and their modifications at the end of treatment; to compare the number of SWM-test points classified as altered for hands and feet before and after treatment; to evaluate the frequency of alteration of the radial, ulnar and median nerves in the hands, and medial plantar, lateral plantar, sural and calcaneal branches of the tibial nerve in the feet by the points tested on SWM-test at diagnosis and at the end of treatment; to correlate the patterns of SWM-test alteration in the diagnosis with the responses to the Leprosy Suspicion Questionnaire (LSQ), as published before [16, 17]; to correlate the patterns of SWM-test changes for hands and feet at diagnosis with anti-PGL-I serology; to correlate the patterns of SWM-test changes for hands and feet at diagnosis and at the end of treatment with the degree of functional disability of the diagnosis and discharge; to correlate the patterns of SWM-test alteration (stable, improvement, worsening) for hands and feet at diagnosis and their clinical-therapeutic evolution at the end.

Subjects and methods

Type of study

This study is a longitudinal, prospective cohort study.

Diagnostic criteria for leprosy

The subjects underwent a standardized clinical dermatoneurological exam according to Brazilian Ministry of Health guidelines as described in previous article from our group. [16, 17]. We classified the patients considering the guidelines adapted by Madrid (Congress of Madrid 1953) [18] and the Indian Association of Leprology (IAL 1982) [19] classifications, as follows: indeterminate (I), polar tuberculoid (T), borderline (B), polar lepromatous (L) and pure neural leprosy (PNL); and broadly classified according to WHO operational criteria [PB (I and T) and MB (B and L)] [16, 20].

Ethics, consent and permissions

This study was approved by the Research Ethics Committee at the Clinical Hospital of Ribeirão Preto Medical School, University of São Paulo (protocol number 2.165.032, MH-Brazil). Written informed consent was obtained from every participant, including the parent/guardian of each participant younger than 18 years old. All procedures involving human subjects comply with the ethical standards of Declaration of Helsinki (1975/2008).

Study sample

The SWM-test was performed by a single dermatologist and leprologist at the beginning and at the end of the treatment of patients diagnosed with leprosy in the municipality of Jardinópolis during the period from 2016 to 2019.

Tactile sensitive test by Semmes-Weinstein Monofilaments (SWM-test)

The SW monofilament kit, consisting of six colored monofilaments, was used. Each color corresponds to a sensation threshold: green (0.07 gf), blue (0.2 gf), violet (2.0 gf), red (4.0 gf), orange (10.0 gf), pink (300 gf).

Considering the skin pressure threshold for one-point static touch was estimated with the SWM. The critical force is the axial force necessary to cause the filament to buckle. Initially, the test with the monofilaments was demonstrated to the patient in an arm area with normal sensation. After this stage, the test began with the SW monofilaments. With the patient’s eyes closed, each monofilament was applied perpendicularly for about 1 to 2 seconds at each skin point inside the respective nerve sensitive territory (dermatome). The pressure on the skin should be applied for 1 to 2 seconds until the filament curvature is reached, not allowing it to slide over the skin [21, 22]. To assess the sensation in the path of the radial, ulnar and median nerves in the hands, and tibial, sural and saphenous nerves in the feet, the monofilament was applied in order to bend over the area without, however, sliding over the patient’s skin. Seven points were evaluated on each hand (Fig 1) and 9 points on each foot (Fig 2). As recommended, the test was initiated by the thinnest monofilament and, therefore, having the lowest pressure (0.07 gf, green monofilament). When there was no response, the blue monofilament (0.2 gf) was used, and so on. The record was made on a simplified neurological assessment form, containing the color of the first filament perceived by the patient.

Fig 1

Dermatomes of the radial, ulnar and median nerves and the 7-SWM-test points tested on the hand.

The normal tactile sensation threshold for the hand corresponds to the green monofilament (0.07 gf).

Fig 2

Dermatomes of the branches of the fibular and tibial nerves and the 11-SWM-test points tested on the foot.

The normal tactile sensation threshold for the foot corresponds to the green and blue monofilaments (0.2 gf).

About unit of measurement, the use of the logarithmic Manufacturer´s filament Number (MN) was shown at least as early as 1978 [23] to be a source of confusion (these authors also pointed out that an engineering approach would require stress rather than pressure as the relevant variable) and was only introduced (by Weinstein) to facilitate the graphic visualization and statistical treatment of results. Bell-Krotoski and Tomancik [24] have long recommended the simple use of the standard monofilament force values as they have repeatedly been shown to provide consistent and useful results for clinical evaluations and follow-ups over time. Thus, we considered the standard monofilament force values (gram-force) for all analyses in this study.

Analysis and interpretation of SWM-test points

The respective points were plotted on an Excel spreadsheet considering the values according to the color of its sensation threshold defined by the SW-monofilament Kit: green (0.07 gf), blue (0.2 gf), violet (2.0 gf), red (4.0 gf), orange (10.0 gf), pink (300 gf). For the black one (when the pink monofilament is not recognized), the value of 400 gf was established for calculation purposes.

For the hands, the sensation to green monofilament (0.07 gf) was considered normal, while for the feet, it was up to the blue one (0.2 gf).

In the spreadsheet, each patient (rows) had its values described point-to-point (columns) in the respective hands and feet at diagnosis and at the end of treatment.

After the distribution of the points, using the Excel “ACCOUNT” tool and applying the criterion “>0.07” for the hand points and “>0.2” for the feet, the total numbers of altered SWM-test points for each hand and foot of each individual, at diagnosis and at the end of treatment, were obtained. From this, we calculated the percentage, the sum, the average, and the maximum value of points altered for each body part.

The Excel “ACCOUNT” tool was used in the analysis of the sample, for each point, applying criteria equal to the respective grammage value of each monofilament, such as “0.07”, “0.2”, “2”, up to “400”. Subsequently, their sum was calculated for the elaboration of graphs (bars and corresponding colors), both for absolute values and percentages, and for pre and post-treatment analysis.

For the analysis of the percentage of altered nerves in the hands and feet at diagnosis and at the end of treatment, the points of the dermatomes of the median (points 1, 2 and 3), ulnar (points 4, 5 and 6) and radial (point 7) nerves were considered for the hands; and the medial plantar branch (points 1, 2, 4, 5, 7), lateral plantar branch (points 3, 6), sural nerve (point 8) and calcaneal branch (point 9), for the feet. With the Excel “ACCOUNT” tool and applying the criterion “>0.07” for the hand points and “>0.2” for the foot ones, the number of altered points corresponding to each aforementioned nerve was obtained.

To analyze the therapeutic evolution of the sample point-by-point, only patients who completed the treatment were considered. All the respective right and left points were placed in a single column. From these values, initially trying to separate the altered points from the normal ones for hands and feet, the difference between the initial and final values was calculated. Its result showed us whether the evolution was “stable” (Δ = 0), if there was “improvement” (Δ>0) or if it was “worse” (Δ<0). Thus, we calculated the percentage of evolution of the points and the respective average percentage of stability, improvement and worsening of all points.

Finally, considering that not all individuals improve their sensation by SWM-test to the point of being considered normal, it becomes important to know how satisfactory or not their evolution was in the analysis, for instance, there is an evolution from 300g, at the beginning, to 4g, at the end of the treatment. Therefore, a legend of points was established for the values of the respective differences between the initial and final assessments, ranging from stable, equal to zero, to +6 (improvement) or to -6 (worsening), as shown in Table 1.

Table 1

Standardization of SWM-test points and values given to the evolutionary differences between them.

Points	Dif.	Point value	Dif.	Point value	Dif.	Point value	Dif.	Point value	Dif.	Point value	Dif.	Point value
400
300	100	1
10	390	2	290	1
4	396	3	296	2	6	1
2	398	4	298	3	8	2	2	1
0.2	399.8	5	299.8	4	9.8	3	3.8	2	1.8	1
0.07	399.95	6	299.95	5	9.95	4	3.96	3	1.98	2	0.15	1

Dif. difference

In the distribution of each point, we calculated the absolute number of points that had the respective evolution (+6 to -6) and their respective percentages within the total point sample.

Assessment of anti-PGL-I titer by ELISA

Indirect ELISA was used to measure the anti-PGL-I IgM titer of every serum sample using the protocol previously reported [16, 17, 25]. The sample index was calculated by dividing their optical density (O.D.) per the established 0.295 cut-off; indexes above 1.0 were considered positive.

Patients’ follow-up

The follow-up of patients diagnosed with leprosy in the municipality of Jardinópolis from 2016 to 2019 was carried out by the dermatologist responsible for the study. The following variables were considered to assess stability, improvement or worsening of dermatological signs: hypochromatic macules with alteration of sensation and/or some dysautonomia, localized irregular patches of circumscribed hair loss and appearance of ichthyosis. In relation to neurological symptoms, the following were considered: electric shock-like pain on nerve palpation, tingling, cramps, numbness and needle sensation.

Statistical analysis

Test-T for paired samples was used to assess asymmetry for each sensation point tested on the right and on the left. The correlation between the sum of the number of altered SWM-test points per individual in the diagnosis and the sum of the number of responses to the LSQ, the values of the anti-PGL-I antibody indexes and the degree of functional disability were analyzed. Finally, the correlation between the sum of the number of altered SWM-test points per individual and the degree of functional disability at the end of the treatment was evaluated. The Binomial Logistic Regression Analysis was performed in order to assess the association age, sex and number of pre-treatment altered SWM-test points with the outcome of having a SWM-test clinical improvement using the jamovi project (2021). jamovi (Version 1.6) [Computer Software]. Retrieved from https://www.jamovi.org.

Results

The demographic characterizations at diagnosis and at the end of treatment, as well as the clinical classification of patients are described in Table 2. All patients were multibacillary, 81 (75.7%) patients had disability at diagnosis, while 34 (45.3%) had some disability at the end of treatment.

Table 2

Demographic characterization and clinical classification of patients.

	Diagnose (n = 107)		End of treatment (n = 76)
Sex	N	%	n	%
Male	48	44.9	34	44.7
Female	59	55.1	42	55.3
Age (years)
Min	6		7
Max	77		78
Average	42.3		42.8
Median	45		45.5
Age range
< 15	10	9.3	7	9.2
15 |— 20	6	5.6	6	7.9
20 |— 30	13	12.1	7	9.2
30 |— 40	17	15.9	12	15.8
40 |— 50	16	15.0	11	14.5
50 |— 60	26	24.3	17	22.4
60 |— 70	12	11.2	11	14.5
≥ 70	7	6.5	5	6.6
Classification
Borderline	101	94.4	70	92.1
Lepromatous	1	0.9	1	1.3
Pure neural leprosy	5	4.7	5	6.6
Degree of disability
0	26	24.3	42	55.3
1	63	58.9	21	27.6
2	18	16.8	13	17.1
Not evaluated	0	-	31	-

Regarding SWM-test, it was performed in 107 patients at diagnosis and in 76 patients at the end of treatment. The reasons for not evaluating patients at the end of treatment are described in Table 3. At diagnosis, 61 patients (57%) had normal SWM-test in the hands and only 13 (12.1%) in the feet. At the end of treatment, 57 (75%) patients had no abnormal point in the hands and 31 (40.8%) in the feet, an improvement differential of 18% for the hands, and 28.7% for the feet.

Table 3

Reasons for not performing SWM-test in 31 patients.

Reasons	n	%
Completed treatment, but did not return for end-of-treatment evaluation	3	9.7
Patients who moved out of town	6	19.4
Leprosy treatment dropout	7	22.6
Refused diagnosis and treatment	1	3.2
Still under treatment	12	38.7
Died before the end of treatment	2	6.5

Out of the 76 patients evaluated at the end of treatment, in 48 (63.2%) of them the number of abnormal SWM-test points to the hands remained stable compared to the initial. On the other hand, there was improvement in 22 (28.9%) of them and worsening in only 6 (7.9%) patients. Regarding the assessment of the feet tactile sensation, the number of abnormal SWM-test points remained stable in 17 (22.4%) patients, while there was an improvement in 47 (61.8%) and worsening in 12 (15.8%) patients.

The improvement in patients’ SWM-test can be assessed by increasing the percentage of points considered normal for the hands (green point = 0.07 gram-force) and feet (green and blue points = 0.2 gf), as well as the decrease in percentages referring to the other points from violet (0.2 gf) to black (300 gf is not recognized) as represented in Figs 3 and 4. The most significant increase was that of green points for the feet at the end of treatment.

Fig 3

Side-by-side distribution of the percentage of the number of SWM-test points of the hands and feet at diagnosis and after the end of treatment of patients diagnosed with leprosy in Jardinópolis from 2016 to 2019.

Fig 4

Percentage distribution of the number of SWM-test points of the upper and lower limbs at diagnosis and after the end of treatment of patients diagnosed with leprosy in Jardinópolis from 2016 to 2019.

Statistical differences were observed in the evolution of the means of the summation of the number of altered points which had been detected by SWM-test performed on the right and left hands and feet of each patient when compared at diagnosis and at the end of treatment with WHO multidrug therapy, except for the left hand (p> 0.07), as shown in Fig 5.

Fig 5

Evolution of the averages of the sum of the number of altered points detected by SWM-test performed on the right and left hands and feet of each patient when compared at diagnosis and at the end of WHO MDT.

Considering the sum of the number of altered SWM-test points distributed in the hands and feet, respectively, for each patient, significant differences were observed in their therapeutic evolution, as shown in Fig 6.

Fig 6

Evolution of the sum of the number of altered SWM-test points in the hands and feet of leprosy patients evaluated at diagnosis and at the end of WHO multidrug therapy in Jardinópolis (SP).

We seek to characterize the point-to-point evolution as stable, worsening (negative values) or improvement (positive values), as described in Table 4, by taking into account that each point could evolve to improvement or worsening, regardless of whether it was characterized as altered or not, that is, a point recognized as 300 gf at diagnosis that became 4 gf at the end of the treatment indicates a significant improvement in sensation, remaining, however, as an altered SWM-test point since it is greater than 0.07 gf for the hands and 0.2 gf for the feet.

Table 4

Variation of the point-to-point evolution by SWM-test of the hands and feet at the end of the leprosy patient treatment in Jardinópolis (SP).

Variation / evolution	SWM-TEST POINTS OF THE HANDS							SWM-TEST POINTS OF THE FEET									TOTAL	%
	PT1	PT2	PT3	PT4	PT5	PT6	PT7	PT1	PT2	PT3	PT4	PT5	PT6	PT7	PT8	PT9
-6	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0.0
-5	0	0	0	0	0	0	0	0	0	0	1	0	1	0	0	0	2	0.1
-4	0	1	1	0	0	0	0	0	0	1	0	0	1	1	0	0	5	0.2
-3	1	2	0	2	0	0	0	1	1	1	2	1	2	1	1	1	16	0.7
-2	2	0	0	0	1	1	0	3	1	1	2	4	3	1	2	2	23	0.9
-1	3	4	6	5	7	9	9	9	7	8	14	9	13	11	20	11	145	6.0
STABLE	125	132	135	132	127	122	122	82	96	83	72	76	62	94	64	45	1569	64.6
1	11	11	7	7	9	8	15	34	28	40	32	32	38	30	40	40	382	15.7
2	7	0	1	0	0	3	3	14	14	11	16	19	21	7	21	25	162	6.7
3	0	1	0	2	5	4	1	6	0	3	7	2	5	1	1	23	61	2.5
4	2	0	2	2	1	2	2	1	1	1	3	3	5	5	1	2	33	1.4
5	0	0	0	0	0	2	0	1	1	1	1	2	0	0	1	3	12	0.5
6	0	1	0	2	2	1	0	1	2	1	2	2	1	1	0	0	16	0.7

In this point-to-point analysis, it was observed that there was an improvement of 27.5% of the points (666), and in 24.9%, the variation was from +1 to +3, while the worsening occurred in only 7.9% of the points (191), with a variation of -1 in 6%, and stability occurred in 64.6% of the points (1569).

The serological result of the anti-PGL-I antibody was positive in 38 (40%) patients, 16 (42.1%) with index ≥2, as shown in Table 5.

Table 5

Results of anti-PGL-I antibody measurements (anti-PGL-I index; cut off 0.295).

	Total (n = 95)
	n	%
Anti-PGL-I < 1 (negative)	57	60.0
Anti-PGL-I ≥ 1 (positive)	38	40.0
1.0 |— 1.5	14	36.8
1.5 |—2.0	8	21.1
≥ 2.0	16	42.1

In Spearman’s correlation analysis, a positive correlation with statistical significance was observed between the number of hand and foot SWM-test altered points at diagnosis and the degree of disability at diagnosis (0.69) and between the number of hand and foot SWM-test altered points and the degree of disability at the end of treatment (0.80). The correlation between the number of hand and foot SWM-test altered points at diagnosis and the Elisa anti-PGL-I index was low (0.027).

The number and percentage of individuals, sum, average and maximum number of SWM-test altered points in the hands and feet at diagnosis and at the end of treatment are described in Table 6.

Table 6

The number and percentage of individuals with altered points in the hands and feet by SWM-test at diagnosis and at the end of treatment, and the sum, average and maximum number of altered points in the hands and feet at diagnosis and at the end of treatment.

	Evaluation at diagnosis				Evaluation at the end of treatment
	Hands		Feet		Hands		Feet
	R	L	R	L	R	L	R	L
n of patients with altered SWM-test points	38	38	90	88	18	17	41	38
% of patients with altered SWM-test points	35.5	35.5	84.1	82.2	23.7	22.4	53.9	50.0
Sum of the number of altered SWM-test points	154	143	416	448	81.0	80.0	171	180
Average of altered SWM-test points/patient	4.1	3.8	4.6	5.1	4.5	4.7	4.2	4.7
Maximum number of altered SWM-test points/patient	7	7.0	9.0	9.0	7.0	7.0	9.0	9.0

n: number; %: percentage; R: right; L: left.

The distribution of the number of altered SWM-test points with the corresponding nerves for hands and feet, before and after treatment, are described in Tables 7–10.

Table 7

Distribution of the number of SWM-test (normal and altered) points of the hands per patient at treatment diagnosis and corresponding nerves.

	Median nerve (Points 1, 2, 3)				Ulnar nerve (Points 4, 5, 6)				Radial nerve (Point 7)
	R		L		R		L		R		L
	N	%	n	%	n	%	n	%	n	%	n	%
No altered point	78	72.9	83	77.6	76	71.0	79	73.8	85	79.4	82	76.6
1 altered point	9	8.4	10	9.3	9	8.4	7	6.5	22	20.6	25	23.4
2 altered points	6	5.6	0	0	6	5.6	4	3.7	-	-	-	-
3 altered points	14	13.1	14	13.1	16	15.0	17	15.9	-	-	-	-
Total	107	100	107	100	107	100	107	100	107	100	107	100

n: number; %: percentage; R: right; L: left.

Table 10

Distribution of the number of SWM-test (normal and altered) points of the feet per patient at the end of the treatment and corresponding nerves.

	Medial plantar branch (Points 1, 2, 4, 5, 7)				Lateral plantar branch (Points 3, 6)				Sural nerve (Point 8)				Calcaneal branch (Point 9)
	R		L		R		L		R		L		R		L
	n	%	n	%	n	%	n	%	n	%	n	%	N	%	n	%
No altered point	51	67.1	50	65.8	56	73.7	55	72.4	52	68.4	57	75.0	37	48.7	40	52.6
1 altered point	4	5.3	5	6.6	9	11.8	7	9.2	24	31.6	19	25.0	39	51.3	36	47.4
2 altered points	6	7.9	2	2.6	11	14.5	14	18.4	-	-	-	-	-	-	-	-
3 altered points	6	7.9	3	3.9	-	-	-	-	-	-	-	-	-	-	-	-
4 altered points	2	2.6	8	10.5	-	-	-	-	-	-	-	-	-	-	-	-
5 altered points	7	9.2	8	10.5	-	-	-	-	-	-	-	-	-	-	-	-
Total	76	100	76	100	76	100	76	100	76	100	76	100	76	100	76	100

n: number; %: percentage; R: right; L: left.

At diagnosis, among all the points evaluated by the respective corresponding nerves considering both sides, the median nerve (3 points each side) presented 115/642 altered SWM-test points (17.9%), the ulnar (3 points each side) presented 135/642 (21.03%) altered SWM-test points, while the radial (single point) presented 47/214 (21.96%) altered SWM-test points. Bilateral alterations were found in 35 (30.4%) median nerves, 47 (34.8%) ulnar nerves and 18 (38.3%) radial nerves. Considering the values obtained by SWM-test for each point, in the upper limbs, corroborating the higher percentage of altered SWM-test points, only point 7 (sensitive radial nerve) showed significant asymmetry (p = 0.04), while among the median (p = 0.15) and the ulnar (p = 0.12) points there was no demonstrated asymmetry.

Additionally, considering the sum of the number of altered SWM-test points in the upper limbs (hands), there was no statistical difference (p = 0.18) between the right and left sides.

At the end of treatment, considering the 76 patients, the median nerve showed 38/456 altered SWM-test points (14.9%), the ulnar nerve showed 56/456 (12.3%) altered SWM-test points, while the radial nerve presented 24/152 (16.9%) altered SWM-test points. Bilateral alterations were found in 35 (30.4%) median nerves, 47 (34.8%) ulnar nerves and 18 (38.3%) radial nerves. Considering the values obtained by SWM-test for each point, in the upper limbs, despite a higher percentage of altered points, point 7 no longer showed significant asymmetry (p = 0.16), like the ulnar nerve (p = 0.12). The median nerves, however, became asymmetrical after treatment (p = 0.009).

In the lower, limbs among all the evaluated points that correspond to the tibial nerve considering both sides, 864 of the 1926 points tested (44.9%) were reported as altered (> 0.2 gf), demonstrating a significant asymmetry (p = 0.005) at diagnosis.

Separating them by the corresponding branches, the medial plantar branch (5 points per side) presented alteration in 436/1070 points (40.7%), the lateral plantar branch in 162/428 points (37.9%), the sural nerve in 111/214 points (51.9%) and the calcaneal branch in 172/214 points (80.4%).

Bilateral alterations were found in 95/436 (21.8%) of the medial plantar branches, 51/162 (31.5%) of the lateral plantar branches, 41/111 (36.9%) of the sural nerves and 80/172 (46.5%) of the calcaneal branches. Considering the values obtained by SWM-test for each point in the lower limbs, the asymmetries within the individual values were statistically significant between the medial plantar branches (p = 0.03) and within the sural nerves (p = 0.003). Nevertheless, within the points of the lateral plantar (p = 0.38) and calcaneal (p = 0.1) branches, there was no demonstrated asymmetry.

Additionally, due to the sum of the number of altered SWM-test points in the lower limbs (feet), the difference also demonstrated significant asymmetry (p = 0.04), which highlights the importance of the tibial nerve for the establishment of asymmetric leprosy neuropathy.

As for the lower limbs (feet), at the end of treatment, there was an important reduction in the percentage of alterations in the medial plantar branch with 167/760 altered SWM-test points (21.9%), the lateral plantar branch with 66/304 points (21/7%), the sural nerve with 43/152 points (28.3%) and the calcaneal branch with 75/152 points (49.3%).

Considering the values obtained by SWM-test for each point in the lower limbs, the asymmetry within the individual values remained statistically significant in the medial plantar branches (p = 0.02). They became asymmetrical within the points of the lateral plantar branches (p = 0.2) and symmetrical in the sural branches (p = 0.13), but they remained symmetrical in the calcaneal branches (p = 0.28).

As for the number of SWM-test points with coinciding bilateral changes, despite a decrease in the number of altered points with the treatment, there was an increase in the percentages, with 61/167 (36.5%) points of the medial plantar branches, 25/66 (37.9%) of the lateral plantar branches, 18/43 (55.8%) of the sural nerves and 36/75 (48%) of the calcaneal branches.

Considering all the points tested in the feet as being from the tibial nerves, a reduction was observed in 351 of the 1368 points tested (25.7%) at the end of treatment. Nevertheless, the asymmetry between the sides remained significant (p = 0.001).

In summary, the distribution of patients by the number of affected limbs at diagnosis defined by SWM-test and the respective averages of the number of altered SWM-test points per limb are shown in Table 11.

Table 11

Distribution of leprosy patients by number of affected limbs as defined by SWM-test and the respective averages of the sum of the number of altered points per limb and their evolution.

n of individuals	n of affected limbs/individual at the diagnose	Average of the sum of the number of altered SWM-test points per limb
		n diagnose				n end of treatment
		RUL	LUL	RLL	LLL	RUL	LUL	RLL	LLL
11	0	0	0	0	0	0.0	0.0	0.1	0.1
12	1	0.5	0.1	0.7	0.4	0.0	0.0	0.5	0.1
40	2	0.0	0.0	3.4	4.0	0.2	0.2	1.2	1.4
14	3	1.2	1.4	4.8	4.9	0.0	0.1	0.7	1.0
30	4	4.4	4.1	6.9	7.2	3.4	3.3	5.0	5.1

n number; RUL right upper limb; LUL left upper limb; RLL right lower limb; LLL left lower limb.

Only 11/107 (10.2%) individuals did not present alterations to SWM-test at diagnosis, among which the clinical and laboratory criteria stood out: hypochromatic macules with alterations in sensation (n = 10), erythematous plaque with alteration in sensation (n = 1), LSQ positivity (n = 9), incomplete endogenous histamine test (n = 6), and positive anti-PGL-I ELISA index (n = 6) with a mean value of 1.4.

The logistic regression model was significant (X2 = 39.0; p<0.001; R2 MacFadden = 0.41; Accuracy = 0.82; Specificity = 0.47; Sensitivity = 0.98; AUC = 0.84), demonstrating an absence of association between age [OR = 1.01 (%CI = 0.97–1.06); p = 0.5], sex [OR = 1.1 (%CI = 0.3–4.4); p = 0.8], number of pre-treatment altered SWM-test points [OR = 0.9 (%CI = 0.8–1.03); p = 0.2] with the clinical outcome (SWM-test clinical improvement). Statistical report is in S1 File.

Discussion

The study mapped alterations in the sensation of the hands and feet by the SWM-test of 107 patients at diagnosis and in 76 patients at the end of treatment for leprosy patients followed in Jardinópolis from 2016 to 2019. The study highlighted alterations in the patterns of hand and foot SWM-test at diagnosis and their consequent modifications to the specific treatment of leprosy with antimicrobial drugs, which defines the infectious (bacterial) etiology of neuropathy and reinforces the importance of using SWM-test in the clinical diagnosis of the disease.

Assessing sensation is especially important for preventing peripheral neuropathy. Semmes-Weinstein monofilaments are widely used in the assessment of tactile sensation in peripheral neuropathies of the upper and lower limbs [14, 22]. Although there is other device to assess the sensation for diagnosis and the follow-up of the neuropathy as the pressure-specified sensory device (PSSD), described by Baltodano et al [26], with perhaps a marginal improvement over the SWM, the major advantages in assessing the sensation of peripheral nerves by using Semmes-Weinstein monofilaments are: its easy application, low cost and the fact that the patient is blindfolded, making it difficult to have false responses in the test [27].

Since it is an infection marked especially by the involvement of peripheral nerves, leprosy causes damage related to sensory, motor, and autonomic functions. Sensitive impairment, present in all forms of the disease, often precedes the involvement of motor function [15]. The best approach for the prevention of neural damage and the consequences caused by leprosy is early diagnosis and appropriate treatment. However, certain patients will still need actions to prevent the progression of the disability, or even rehabilitation measures [6, 28]. This group may consist of the following cases: new cases already detected with some disability; cases that will develop some type of disability during or after the end of treatment, and old cases diagnosed late with disability already installed [29].

Regarding demographic characteristics, the number of female patients was higher than that of male patients, in contrast to the official Brazilian data 2014–2018, with higher rates among men than women in all age groups. The distribution of patients by age group followed the same patterns of the Brazilian data [30]. The high number of diagnoses in children under 15 years of age (9.3%), all patients being multibacillary, the high number of patients with disability at diagnosis and the high seroprevalence of anti-PGL-I are evidence of hidden endemicity revealed in the Jardinópolis municipality during the research period, as already demonstrated in the literature [16, 20].

Hand and foot SWM-test at the end of treatment was not performed in 31 (29.0%) patients. Despite having completed the 12-month treatment, three patients did not return for the discharge assessment. These patients were actively searched, but they were not found. Regarding the 6 patients who moved away from Jardinópolis, a medical report was made available, in addition to immediate communication from the State’s epidemiological surveillance network. Despite the presence of a dermatologist/leprologist in patient care, there was a high number (22.6%) of treatment dropout. Leprosy treatment dropout occurs due to several factors, among them: lack of knowledge about the disease, turnover of health professionals, reaction episodes, worsening of neurological symptoms, especially in the first months of treatment, side effects of the treatment and the lack of credibility in leprosy cure [31]. The patient who refused the diagnosis and treatment had multiple hypo-anesthetic hypochromatic and anhydrotic macules with histamine areflexia, besides positive PCR for Mycobacterium leprae in slit skin smear. At the departure of the dermatologist from the municipality, in November 2019, 12 patients were still undergoing leprosy treatment. The deaths of 2 patients were due to complications of chronic obstructive pulmonary disease in a smoking patient and stroke in a hypertensive and diabetic patient.

Cutaneous innervation of the hands is done by the median, ulnar and radial nerves. The innervation of the dorsum of the foot and the lateral face of the leg is performed by the lateral sural cutaneous, superficial fibular, lateral dorsal cutaneous and deep fibular branches of the common fibular nerve. The cutaneous innervation of the plantar region is performed by branches of the tibial nerve, such as: calcaneal, medial plantar, lateral plantar and saphenous [32]. SWM-test of the hands and feet allows the mapping of tactile sensation thresholds in the path of the radial, ulnar and median nerves in the hands, and tibial and common fibular nerves in the feet, providing a record that can be easily compared and interpreted, both in diagnosis and in its therapeutic evolution. In the upper limbs, it is important to highlight the importance of point 7 (radial nerve), which was significantly asymmetrical. In the lower limbs (feet), it is worth noting that the difference between the sum of altered SWM-test points showed significant asymmetry (p = 0.04) when comparing the sides, which highlights the importance of the tibial nerve for the establishment of asymmetric leprosy neuropathy. In addition, the asymmetry defined in point 8 exclusively reinforces the focus of the aggression, which associated with the asymmetry of SWM-test alterations are characteristic of leprosy neuropathy.

The greater involvement of the nerves of the lower limbs, represented by the higher frequency of altered SWM-test points on the feet, both before and after treatment, differs from the previous literature, which suggests that the nerves of the upper limbs are affected more frequently than the lower ones [12, 33]. Several studies demonstrate that among the nerves that showed the highest frequency of involvement, assessed by electroneuromyography, there are: the ulnar, the superficial radial, the sural, the superficial fibular, the sensitive tibial; and those which presented the lowest frequencies are: the common fibular nerve and the median [4-12].

The data on the prevalence of neural impairment in leprosy are controversial and vary according to the region, the instruments of detection and the evaluation criteria. It is worth mentioning that only the points of the plantar region that are correlated to the dermatomes of the tibial nerve branches were tested. Such nerve is not usually addressed in the conventional electroneuromyography exam, and, undoubtedly, it becomes the most affected nerve in leprosy.

The points on the dorsum of the foot, point 10 (deep fibular nerve) and point 11 (sural nerve), which are relative to the dermatomes of the branches of the common fibular nerve, were not tested. Thus, it is estimated that the involvement of the nerves of the lower limbs is even greater.

All patients were treated with a standard multibacillary multidrug (MDT/WHO) regimen, consisting of the respective antimicrobial drugs and doses, namely: monthly supervised dose with 600 mg rifampicin + 100 mg dapsone + 300 mg clofazimine, and self-administered daily dose with 100 mg dapsone + clofazimine 50 mg. Early diagnosis and treatment prevents permanent loss of neural function. Mycobacterium leprae has tropism for the peripheral nerves, binding to Schwann cells, in such a way that it induces demyelination [30]. Therefore, the improvement in neurological symptoms and patients’ SWM-test, represented by the increase in the percentage of points considered normal for the hands (green point = 0.07 g-f) and feet (green and blue points = 0.2 g-f), as well as the decrease in the percentages referring to the other points from violet (2 g-f) to black (it does not recognize 300 g-f), with antibiotic treatment is strong evidence of the infectious etiology of peripheral neuropathy and it is very valuable in the follow-up of leprosy patients, especially in those with laboratory tests (SSS and skin biopsy) without the identification of M. leprae.

These findings are corroborated by the significant 31% reduction in the degree of functional disability after treatment, in addition to the 26% average reduction in the number of altered SWM-test points in the feet, with emphasis on the calcaneal branch of the tibial nerve, while an average reduction of 7.5% of the points of the hands specially in the ulnar nerve. Moreover, in the point-to-point analysis, the SWM-test evolution at the end of the treatment showed an improvement in 27.5% of all the points analyzed, varying from 1 to 3 levels of weight in 25% of these points.

Although the Leprosy Suspicion Questionnaire has proved to be an important tool in the leprosy diagnosis, essentially due to the neurological complaints of numbness, tingling, nerve pain, among others [16, 17], there was no correlation between the sum of the number of questions to the LSQ and the number of altered points to the hand and foot SWM-test, which denotes the multiple and multifocal character of leprosy neuropathy.

Considering the distribution of the sample by limb involvement and the respective averages of the sum of the number of altered SWM-test points, it is worth highlighting that only 10.2% of the patients did not present changes to the SWM-test at diagnosis; however other clinical and laboratory criteria had already defined diagnosis, which demonstrates the importance of this tool for the definition of neuropathy and leprosy diagnosis in approximately 90% of cases.

In addition, the reduction in the values of these averages after the end of multidrug therapy demonstrates to what extent the treatment was able to modify the sensation profile, especially of the feet of these patients, and the most marked improvement being was evident among patients with fewer affected limbs, reaffirming the proposition that early diagnosis and treatment are essential in preventing deformities and disability. It is worth emphasizing that those patients who, even after multidrug therapy, still have residual disability detected by the SWM test, may benefit from appropriate peripheral nerve decompression surgery, preventing definitive neural damage from leprosy, as described by Wan et al [34, 35]. Furthermore, considering the binomial logistic regression analysis, we emphasize that regardless of the initial severity weight based on the number of altered SWM-test points, the treatment was undoubtedly able to recover the sensation of hands and feet.

Conclusion

The tactile sensation test using Semmes-Weisntein monofilaments proved to be an important instrument for defining peripheral neuropathy of leprosy patients in the study, affecting 89.7% (96) of them and reaching 1 to 4 limbs. 19.8% of the altered SWM-test points in the hands, and 44.8% in the feet were detectable, evolving to 15.1% in the hands and to 25.6% in the feet at the end of the treatment. Both variations had statistical significance.

At diagnosis, using the hand and foot SWM-test criteria, the tibial was the most affected nerve by leprosy, mainly in the calcaneal (80.4%) and sural branches (52%). However, the asymmetries were significant regarding the values of the medial plantar (points 1, 2, 4, 5, and 7) and the sural (points 3 and 6) branches. In the hands, the nerve with the highest absolute number of affected points was the ulnar, even though, in percentage, the radial nerve was not only more affected, but also the only definer of asymmetry.

There was neither satisfactory correlation between the patterns of SWM-test alteration at diagnosis and the responses to the LSQ nor in relation to the results of anti-PGL-I serology. Nevertheless, there was a significant positive correlation with the degree of functional disability at diagnosis (0.69) and at the end of treatment (0.80).

SWM-test in point-to-point analysis showed improvement in 27.5% of the points with antimicrobial treatment ranging from 1 to 3 points in graduation, worsening in only 7.9% of the points and stability in 64.9% of the points.

Finally, hand and foot tactile sensation test using Semmes-Weinstein monofilaments proved to be effective in establishing the asymmetric and focal sensitive neuropathic pattern, constituting an important complementary exam in leprosy diagnosis, besides reaffirming its role in the documentation and proof of the therapeutic efficacy of MDT, a low-cost and easy-to-implement instrument which should be an indispensable tool for health care professionals, both in primary and specialized care in leprosy.

Statistical report.

(PDF)

Click here for additional data file.

(XLSX)

Click here for additional data file.

3 Aug 2021

PONE-D-21-17910

Semmes-Weinstein Monofilament esthesiometry for the definition of patterns of sensitivity alteration of the hands and feet in leprosy diagnosis and monitoring

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Reviewer #1: Congratulation to the authors for their study “Semmes-Weinstein Monofilament esthesiometry for the definition of patterns of sensitivity alteration of the hands and feet in leprosy diagnosis and monitoring”. Overall the manuscript is insightful and contributes to the subject of nervous impairment in leprosy patients, specifically MB. The study is very detailed and meticulous. It addresses some gaps found in literature. However, we do have some concerns worth addressing:

1. You state repeatedly throughout the manuscript that you only included multibacillary (or “lepromatous”) cases of leprosy in the study. However, Table 2 details how 101 patients from the initial population were actually classified as Borderline. Therefore, I must inquire:

- Which diagnostic criteria did you use to define the patients? The WHO classification, The Ridley-Jopling classification? (PMID: 17366457) Please define in Materials and Methods, for the sake of clarity.

- Why did you decide not to include patients with paucibacillary leprosy in this study? This should also be stated in the manuscript for the sake of transparency. Perhaps include it as one of the limits of the study.

2. You stress the importance of tibial involvement in leprosy, which is not something new to date. You should consider better implementing what is already known in literature and discuss it in the manuscript (PMID: 4795534, which is also specific for MB patients, and PMID: 11391190).

3. You analyse the esthesiometric improvement in the tested nerves after treatment with WHO regimen. However, not all included patients started with the same severity. In fact, you should consider implementing a multivariate statistical analysis to understand the weight of severity on sensory recovery after treatment. Perhaps also consider evaluating the effects of age and gender as well.

4. You should better discuss the limitations in the study’s methodology. Specifically, you should at least mention alternatives that have been deemed superior in esthesiometric assessments, even if for different purposes, such as the PSSD (PMID: 26220428, PMID: 32128706).

5. The way serology and anti-PDL-1 positivity affected esthesiometric changes is unclear. Although it is true that some evidence suggests that it could be a useful tool for evaluating the efficacy of treatment (i.e. higher serology levels in untreated patients) [PMID: 19784481], one must wonder how relevant is this section for the purpose of your study? Especially considering that correlation index was found to be low.

6. Some minor critiques to the content of the manuscript should also be addressed:

• Consider implementing the type of study (i.e. cohort study) in the title of the manuscript;

• Introduction is not engaging enough, too long and too focused on academic concepts which add very little to the manuscript. Consider reworking it in order to make it more focused on the aims and endpoints of the study;

• Consider moving the following sections of the manuscript to the Discussion: “In a series of studies […] fibular nerve and the median” (p. 4, lines 75-80);

• Consider moving the following sections of the manuscript to the Materials and Methods: “The standard esthesiometer kit […] the dermatomes of each nerve” (p. 4-5, lines 84-92); “All patients were treated […] + clofazimine 50 mg” (p. 26, lines 474-477).

• Finally, some very minor language concerns: “focallity” instead of focality (p.3, line 44); “surreal” instead of sural (p. 22, line 375). Please do consider using a native English speaker for a quick grammar and spelling check.

Reviewer #2: 1)there is very little that is new in in this manuscript. The SWM(S"deemmes-Weinstein monofilament)and ball point pen and the PSSD (pressure-specified sensory device) have been reported almost endlessly to show that medical management is effective. This study does confirm these classic findings , and yet there is no reference to this, espeially not even one mention of the PSSD, which has been shown to be more sensitive in identifying early cases of Leprosy. At the end, I will include a few references that must be added

2) I am sorry to point out all that the SWM estimates the sensibility of a point of skin. it does not make a true measurement. As this paper proves, a set of 6 filaments were used, and therefore there are no normative data but an estimate of a range. Did each filament chosen as the correct one for that point of skin have the number of the filament,, for example 2.83, first converted from its logarithmic form before statistics That number on the filament is the force (not pressure) of that piece of skin and is the log to the base 10 of that force in 0.1mg. So if pressure is going to be discussed, each measurement of force must be changed to pressure by dividing by the diameter of the filament used.

3) The SWM measures sensibility of a piece of skin and yet the authors refer to these as dermatomes. Clearly they are measuring a piece of the skin territory of a peripheral nerve, and not a dermatome. See Figures 1 and 2 for example as well as the text.

4) rather paper should say skin pressure threshold for one point static touch was estimated with the SWM.

when the above is cleared up, and tables, corrected, and numerical pressure not force values are used, I am happy to reconsider this paper

here are recent articles showing what these authors show with medical treatment, but these apply to nerve decompression, which is the disability these patients have after medical treatment (also not mentioned in this paper)

Baltodano, PA, Wan, E, Noboa, J, Rosson, GD, Dellon, AL, Selecting a Test for

Leprous Neuropathy Screening, J Reconstr Microsurg, 31:607-613, 2015.

Wan, E, Rivadeniera, AF, Serrano, HA, Napit, I, Garbino, JA, Joshua, J, Cardona-Castro, N,

Dellon, AL, Theuvenet, W, Protocol for a randomized controlled trial investigating

decompression for leprous neuropathy (the DELN protocol), Lepr Rev, 87:553-561,2016.

Wan, EL, Noboa, J., Baltodono, PA, Jousin, RM, Erickson, W, Wilton, JP, Rosson, GD,

Dellon, AL, Nerve decompression for leprous neuropathy: A prospective study from

Ecuador, Lepr Review, 88:95-108, 2017.

**********

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25 Aug 2021

August 25, 2021.

Fabio Santanelli, di Pompeo d'Illasi, MD, PhD

Academic Editor

PLOS ONE

Sub: PONE-D-21-17910

Dear Editors,

We would like to thank you for all comments about our manuscript: “Semmes-Weinstein Monofilament esthesiometry for the definition of patterns of sensitivity alteration of the hands and feet in leprosy diagnosis and monitoring” because they appointed some important aspects to improve it.

The requested edits were considered and they are in a red in the manuscript. At the end of this authors’ responses is the statistical report. We also included the statistical report as a supporting information file.

Yes, I received support for my study from all of the following sources:

-WHO Implementation Research Team of Ribeirão Preto Medical School

-Center of National Reference in Sanitary Dermatology focusing on Leprosy of Ribeirão Preto Clinical Hospital

-Brazilian Health Ministry (MS/FAEPAFMRP-USP)

-Fiocruz Ribeirão Preto - TED 163/2019

Yes, you can update my Financial Disclosure statement as follows on my behalf:

"This study was supported by the WHO Implementation Research Team of Ribeirão Preto Medical School in the form of a grant awarded to MACF (771/2016 SCAPIR), the Center of National Reference in Sanitary Dermatology focusing on Leprosy of Ribeirão Preto Clinical Hospital, Ribeirão Preto, São Paulo, Brazil in the form of funds awarded to MACF, the Brazilian Health Ministry (MS/FAEPAFMRP-USP) in the form of grants awarded to MACF (749145/2010, 767202/2011), and Fiocruz Ribeirão Preto - TED 163/2019 in the form of a grant awarded to MACF (Processo: N° 25380.102201/2019-62/ Projeto Fiotec: PRES-009-FIO-20)."

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Congratulation to the authors for their study “Semmes-Weinstein Monofilament esthesiometry for the definition of patterns of sensitivity alteration of the hands and feet in leprosy diagnosis and monitoring”. Overall the manuscript is insightful and contributes to the subject of nervous impairment in leprosy patients, specifically MB. The study is very detailed and meticulous. It addresses some gaps found in literature. However, we do have some concerns worth addressing:

1. You state repeatedly throughout the manuscript that you only included multibacillary (or “lepromatous”) cases of leprosy in the study. However, Table 2 details how 101 patients from the initial population were actually classified as Borderline. Therefore, I must inquire:

- Which diagnostic criteria did you use to define the patients? The WHO classification, The Ridley-Jopling classification? (PMID: 17366457) Please define in Materials and Methods, for the sake of clarity.

Author’s comments: Sure, you are right. We did not consider describe about it in the manuscript. In lines 102 to 109, we have added:

Diagnostic criteria for leprosy

The subjects underwent a standardized clinical dermatoneurological exam according to Brazilian Ministry of Health guidelines as described in previous article from our group. [16,17]. We classified the patients considering the guidelines adapted by Madrid (Congress of Madrid 1953) [18] and the Indian Association of Leprology (IAL 1982) [19] classifications, as follows: indeterminate (I), polar tuberculoid (T), borderline (B), polar lepromatous (L) and pure neural leprosy (PNL); and broadly classified according to WHO operational criteria [PB (I and T) and MB (B and L)] [16,20].

- Why did you decide not to include patients with paucibacillary leprosy in this study? This should also be stated in the manuscript for the sake of transparency. Perhaps include it as one of the limits of the study.

Author’s comments: Thanks for your comment. Following the classification criteria based on both cutaneous and nerve evaluations by the specialist, the clinical classification of the patients as paucibacillary become difficult because most of the patients presented more than one nerve impairment added to skin signs of leprosy.

2. You stress the importance of tibial involvement in leprosy, which is not something new to date. You should consider better implementing what is already known in literature and discuss it in the manuscript (PMID: 4795534, which is also specific for MB patients, and PMID: 11391190).

Author’s comments: Thanks for your comment. We highlighted the importance of the tibial involvement in leprosy patients as compared to other nerves mainly to upper limbs. Both articles that you mentioned described interesting studies about tibial nerve exclusively different of our goal to show the importance of esthesiometric tool for the timely diagnosis of leprosy.

About the papers, the first paper by Swift et al (1973), they studied only about the motor conduction velocity, and they did not study the sensory nerves. On the other hand, on the paper from Richard et al (2001), they selected nine leprosy patients with exclusive tibial nerve palsy causing a loss of protective sensation on the sole of the foot, and they considered a very late loss of sensation defined only when they not feeling a 10-g monofilament in at least three sites on the foot.

3. You analyse the esthesiometric improvement in the tested nerves after treatment with WHO regimen. However, not all included patients started with the same severity. In fact, you should consider implementing a multivariate statistical analysis to understand the weight of severity on sensory recovery after treatment. Perhaps also consider evaluating the effects of age and gender as well.

Author’s comments: We thank you for your considerations to improve our paper. We have made the multivariate statistical analysis using a binomial logistic regression analysis, and to get a good performance of this statistical model we considered as independent variables age, sex, number of altered esthesiometric points in pre-treatment, the score of sensory recovery (0 to 5 according each five recovered points), and finally as outcome the esthesiometric clinical improvement (dependent variable) which it was established by the difference between the summation of the number of pre-treatment altered points and the post-treatment ones becoming to nominal variable.

The logistic regression model was significant (X2=39.0; p<0.001; R2 MacFadden=0.41; Accuracy=0.82; Specificity=0.47; Sensitivity=0.98; AUC=0.84), demonstrating an absence of association between age [OR=1.01 (%CI=0.97-1.06); p=0.5], sex [OR=1.1 (%CI=0.3-4.4); p=0.8], number of pre-treatment altered esthesiometric points [OR=0.9 (%CI=0.8-1.03); p=0.2] with the clinical outcome (esthesiometric clinical improvement). Therefore, independent of weight of severity of number of altered esthesiometric points in pre-treatment, after the treatment the sensory recovering happened.

In summary, we improved the manuscript adding:

1) Statistical analysis topic: lines 228-231: “The Binomial Logistic Regression Analysis was performed in order to assess the association age, sex and number of pre-treatment altered esthesiometric points with the outcome of having a esthesiometric clinical improvement using the jamovi project (2021). jamovi (Version 1.6) [Computer Software]. Retrieved from https://www.jamovi.org.”

2) Results topic: lines 410-414: “The logistic regression model was significant (X2=39.0; p<0.001; R2 MacFadden=0.41; Accuracy=0.82; Specificity=0.47; Sensitivity=0.98; AUC=0.84), demonstrating an absence of association between age [OR=1.01 (%CI=0.97-1.06); p=0.5], sex [OR=1.1 (%CI=0.3-4.4); p=0.8], number of pre-treatment altered esthesiometric points [OR=0.9 (%CI=0.8-1.03); p=0.2] with the clinical outcome (esthesiometric clinical improvement).”

3) In the end of the discussion topic: lines 533-535. “…Furthermore, considering the binomial logistic regression analysis, we emphasize that regardless of the initial severity weight based on the number of altered esthesiometric points, the treatment was undoubtedly able to recover the sensitivity of hands and feet.”

4. You should better discuss the limitations in the study’s methodology. Specifically, you should at least mention alternatives that have been deemed superior in esthesiometric assessments, even if for different purposes, such as the PSSD (PMID: 26220428, PMID: 32128706).

Author’s comments: Sure, you are right. We mentioned about this method to assess the sensitivity as PSSD as described by Baltodano et al (2015) in the second paragraph of discussion. (lines 426-429).

We have added the (red) test below:

“…Although there is other device to assess the sensitivity for diagnosis and the follow-up of the neuropathy as the PSSD (pressure-specified sensory device), described by Baltodano et al (2015), with perhaps a marginal improvement over the SWM, the major advantages using Semmes-Weinstein monofilaments are: its easy application, low cost and the fact that the patient is blindfolded, making it difficult to have false responses in the test [27].”

5. The way serology and anti-PDL-1 positivity affected esthesiometric changes is unclear. Although it is true that some evidence suggests that it could be a useful tool for evaluating the efficacy of treatment (i.e. higher serology levels in untreated patients) [PMID: 19784481], one must wonder how relevant is this section for the purpose of your study? Especially considering that correlation index was found to be low.

Author’s comments: Thanks for your comments. About this point of view, we highlighted that we found around 82% of patients (Table 6) with some altered esthesiometric point while the anti-PGL-I positivity was 40% only (Table 5).

6. Some minor critiques to the content of the manuscript should also be addressed:

• Consider implementing the type of study (i.e. cohort study) in the title of the manuscript;

Author’s comments: Thank you so much about this comment. Really, this new title will improve the quality and importance of our work. We changed the title to:

“Semmes-Weinstein Monofilament esthesiometry for the definition of patterns of sensitivity alteration of the hands and feet in a cohort leprosy study”

• Introduction is not engaging enough, too long and too focused on academic concepts which add very little to the manuscript. Consider reworking it in order to make it more focused on the aims and endpoints of the study;

Author’s comments: Thanks for your comment. We agreed with you. We cut the firs paragraph completely and changed a bit the second one. Additionally, considering the comment below, we moved the cited paragraph to the discussion part.

• Consider moving the following sections of the manuscript to the Discussion: “In a series of studies […] fibular nerve and the median” (p. 4, lines 75-80);

Author’s comments: Answered above.

• Consider moving the following sections of the manuscript to the Materials and Methods: “The standard esthesiometer kit […] the dermatomes of each nerve” (p. 4-5, lines 84-92); “All patients were treated […] + clofazimine 50 mg” (p. 26, lines 474-477).

Author’s comments: Thanks a lot. We have moved them for the methods.

• Finally, some very minor language concerns: “focallity” instead of focality (p.3, line 44); “surreal” instead of sural (p. 22, line 375). Please do consider using a native English speaker for a quick grammar and spelling check.

Author’s comments: Thanks a lot. We changed them.

Reviewer #2:

1)there is very little that is new in in this manuscript. The SWM(S"deemmes-Weinstein monofilament)and ball point pen and the PSSD (pressure-specified sensory device) have been reported almost endlessly to show that medical management is effective. This study does confirm these classic findings , and yet there is no reference to this, espeially not even one mention of the PSSD, which has been shown to be more sensitive in identifying early cases of Leprosy. At the end, I will include a few references that must be added

Author’s comments: Sure, thanks a lot for your comment. We mentioned about this method to assess the sensitivity as PSSD as described by Baltodano et al (2015) in the second paragraph of discussion. (lines 426-429).

We have added the (red) test below:

“…Although there is other device to assess the sensitivity for diagnosis and the follow-up of the neuropathy as the PSSD (pressure-specified sensory device), described by Baltodano et al (2015), with perhaps a marginal improvement over the SWM, the major advantages using Semmes-Weinstein monofilaments are: its easy application, low cost and the fact that the patient is blindfolded, making it difficult to have false responses in the test [27].”

2) I am sorry to point out all that the SWM estimates the sensibility of a point of skin. it does not make a true measurement. As this paper proves, a set of 6 filaments were used, and therefore there are no normative data but an estimate of a range. Did each filament chosen as the correct one for that point of skin have the number of the filament,, for example 2.83, first converted from its logarithmic form before statistics That number on the filament is the force (not pressure) of that piece of skin and is the log to the base 10 of that force in 0.1mg. So if pressure is going to be discussed, each measurement of force must be changed to pressure by dividing by the diameter of the filament used.

Author’s comments: Thanks a lot. We agree with you, but some points should be clarified according to the references below:

The SWM test uses a subjective approach to evaluate the threshold of sensitivity of an area of skin: “does the patient perceive the application of a standard filament of specific critical force?” The critical force is the axial force necessary to cause the filament to buckle. The pressure over a nerve ending or group can be estimated, if necessary, for purposes of comparison, either by dividing the filament’s critical force by the area of the tip of the filament in contact with the skin during application, (possibly varying during application) or by the estimated area of skin which is effectively depressed over the relevant nerve endings during the application. Traditionally the calculation is simply Critical Force / Tip Area.

The use of the logarithmic Manufacturer´s filament Number (MN) was shown at least as early as 1978 (Levin S, et al.) to be a source of confusion (these authors also pointed out that an engineering approach would require Stress rather than Pressure as the relevant variable), and was only introduced (by Weinstein) to facilitate the graphic visualization and statistical treatment of results. It certainly does not help to convert the traditional MN numbers back to gram force values as they have long become irrelevant. For example, the widely used 10 gram-force filament, chosen by Birke and Sims in 1986 to identify the threshold between presence or absence of protective sensation in the plantar surface of the foot, would have to be renumbered “5.00” instead of the much-vaunted “5.07”, which is the log value for 11.749 grams-force. Incidentally, the filament cited in that paper as “75 grams” is quoted as having the MN 6.10, which would suggest that they may have been using a 125 gram filament.

On the other hand, Bell-Krotoski and others have long recommended the simple use of the standard monofilament force values as they have repeatedly been shown to provide consistent and useful results for clinical evaluations and follow-ups over time. The pressure applied or stress does not need to be imposed as if it were a more scientific measure.

LEVIN, S; PEARSALL, G; RUDERMAN, R J. Von Frey's method of measuring pressure sensibility in the hand: an engineering analysis of the Weinstein-Semmes pressure aesthesiometer. The Journal of hand surgery, v. 3, n. 3, p. 211-216, 1978.

BIRKE, J. A.; SIMS, D. S. Plantar sensory threshold in the ulcerative foot. Leprosy review, v. 57, n. 3, p. 261-267, 1986.

PFAU, D. B., HAROUN, O., LOCKWOOD, D. N., MAIER, C., SCHMITTER, M., VOLLERT, J., ... & TREEDE, R. D. Mechanical detection and pain thresholds: comparability of devices using stepped and ramped stimuli. Pain Reports, 5(6), 2020.

BELL-KROTOSKI, J., & TOMANCIK, E. The repeatability of testing with Semmes-Weinstein monofilaments. The Journal of hand surgery, 12(1), 155-161. 1987.

3) The SWM measures sensibility of a piece of skin and yet the authors refer to these as dermatomes. Clearly they are measuring a piece of the skin territory of a peripheral nerve, and not a dermatome. See Figures 1 and 2 for example as well as the text.

Author’s comments: Thanks for your comments. We changed the manuscript to become clear our message about the esthesiometry.

Lines 130-132: With the patient’s eyes closed, each monofilament was applied perpendicularly for Lines 151-157: about 1 to 2 seconds at each skin point inside the respective dermatome area.

We changed the title of the Figures 1 and 2.

4) rather paper should say skin pressure threshold for one point static touch was estimated with the SWM.

Author’s comments: Sure, we have added this message into the paragraph starting in line 127

“Considering the skin pressure threshold for one-point static touch was estimated with the SWM. Initially, the test with the monofilaments was demonstrated to the patient in an arm area with normal sensitivity. After this stage, the test began with the SW monofilaments. With the patient’s eyes closed, each monofilament was applied perpendicularly for about 1 to 2 seconds at each skin point inside the respective nerve sensitivity territory (dermatome).”

when the above is cleared up, and tables, corrected, and numerical pressure not force values are used, I am happy to reconsider this paper

Author’s comments: We understood your point of view, but about it, we clarified in Methods (lines 142-149) why we have used the standard monofilament force values as proposed by Bell-Krotoski et al (1987).

here are recent articles showing what these authors show with medical treatment, but these apply to nerve decompression, which is the disability these patients have after medical treatment (also not mentioned in this paper)

Baltodano, PA, Wan, E, Noboa, J, Rosson, GD, Dellon, AL, Selecting a Test for

Leprous Neuropathy Screening, J Reconstr Microsurg, 31:607-613, 2015.

Wan, E, Rivadeniera, AF, Serrano, HA, Napit, I, Garbino, JA, Joshua, J, Cardona-Castro, N,

Dellon, AL, Theuvenet, W, Protocol for a randomized controlled trial investigating

decompression for leprous neuropathy (the DELN protocol), Lepr Rev, 87:553-561,2016.

Wan, EL, Noboa, J., Baltodono, PA, Jousin, RM, Erickson, W, Wilton, JP, Rosson, GD,

Dellon, AL, Nerve decompression for leprous neuropathy: A prospective study from

Ecuador, Lepr Review, 88:95-108, 2017.

Author’s comments: Thanks a lot. We have cited Baltodano et al (2015) above and we included the last ones changing the last paragraph of discussion to:

“In addition, the reduction in the values of these averages after the end of multidrug therapy demonstrates to what extent the treatment was able to modify the sensitivity profile, especially of the feet of these patients, and the most marked improvement being was evident among patients with fewer affected limbs, reaffirming the proposition that early diagnosis and treatment are essential in preventing deformities and disability, avoiding the need for decompression surgery to prevent neural damage in leprosy as described by Wan, EL et al (2016 and 2017).”

Thank you for your consideration. I look forward to hearing from you.

Sincerely,

Submitted filename: Author Responses Aug 25, 2021.docx

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13 Jan 2022

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Reviewer #2: SWM “esthesiometry” Leprosy Rev 2021

1. The title of the paper and throughout the paper misuses “esthesiometry” and “sensitivity” and these need to be changed throughout the paper.

The SWM estimate a range for one-point static touch sensibility, not sensitivity.

Esthesiometry is the measurement of tactile sensibility

The SWM cannot measure tactile sensibility and hence they cannot do esthesiometry,

even if this how the literature has misused these terms in the past. Time for perhaps

this paper to use the terms correctly.

Their title therefore might be: Evaluation of altered patterns of touch sensibility in

Leprosy using the Semmes-Weinstein monofilaments, and short title might me Patterns

of Sensibility in Hands and Feet of Leprosy Patients.

2. Abstract: This sensation is an example of how difficult it is to express what the authors are trying to say. They state “a 18% improvement in tactile sensitivity for the hands, and 28.7% for the feet was detected.” What can this possibly mean. Do they mean that 18% of their total number of hand patients had an improvement in sensation, or do they mean that the pre-treatment mean measurement has improved 18% for the hand.

3. Abstract: the next line is very confusing also: “In the hands, by esthesiometry, radial nerve was significantly asymmetric, while in the feet, the difference between the sum of altered esthesiometric points showed significant asymmetry when comparing both sides, highlighting the tibial nerve for the establishment of asymmetric leprosy neuropathy.” Can even the authors understand what this means????

4. The word “sensitivity” is still in this manuscript. Sensitivity is a statistical term as in sensitivity versus specificity. They use it wrongly when they should be saying sensibility.

5. Conclusion: Sadly ,the authors FAIL to discus that the remaining disability these patients have is due to chronic nerve compression, which can be helped by surgical decompression. They must emphasize that while the r value of .80 is great after triple drug therapy, r2 = 64 which means that 36% of meaning is unexplained or not improved. Those patients after triple drug therapy have residual disability that appropriate peripheral nerve surgery can help. References to this fact were added as refs 34 and 35 at the very last lines of the Discussion, however only to say that drug therapy can reduce the need for surgery, rather than adding the remaining patients would benefit from surgery, and this needs to be emphasized.

a) Wan, EL, Rivadeniera, AF, Jousin, RM, Dellon, AL, Treatment of Peripheral Neuropathy in Leprosy: The case for nerve decompression, Plast Reconstr Surg GO, 2016; 4:e637; doi10.1097/GO0000000000000641.

b) Wan, E, Rivadeniera, AF, Serrano, HA, Napit, I, Garbino, JA, Joshua, J, Cardona-Castro, N, Dellon, AL, Theuvenet, W, Protocol for a randomized controlled trial investigating decompression for leprous neuropathy (the DELN protocol), Lepr Rev, 87:553-561, 2016.

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24 Jan 2022

I put here specifically answers for the questions from the Reviewer #2 (also better writing in the attached document "response to reviewers")

1. The title of the paper and throughout the paper misuses “esthesiometry” and “sensitivity” and these need to be changed throughout the paper.

The SWM estimate a range for one-point static touch sensibility, not sensitivity.

Esthesiometry is the measurement of tactile sensibility.

The SWM cannot measure tactile sensibility and hence they cannot do esthesiometry,

even if this how the literature has misused these terms in the past. Time for perhaps

this paper to use the terms correctly.

Their title therefore might be: Evaluation of altered patterns of touch sensibility in

Leprosy using the Semmes-Weinstein monofilaments, and short title might me Patterns

of Sensibility in Hands and Feet of Leprosy Patients.

Author’s comments: Thanks a lot, to advertise us about our writing and meanings. We have changed the title for: “Evaluation of altered patterns of tactile sensation in the diagnosis and monitoring of leprosy using the Semmes-Weinstein monofilaments” becoming shorter than before and maintained the main idea. Also, we changed the short title as your suggestion to: Hands and feet sensation patterns in leprosy. Therefore, as we have used in our works before in neuropathy field, we used the term “sensitivity” (the quality or condition of being sensitive), instead of “sensibility” (the ability to appreciate and respond to complex emotional or aesthetic influences). By the way, the term “sensation” is used very frequently also, and we decided to change for. On the other hand, we would like to maintain “diagnosis and monitoring” because we have used SWM for monitoring leprosy neuropathy during the leprosy treatment a long time, but our data demonstrated that the SWM also can help the health professionals to stablish the pattern of the leprosy neuropathy diagnosis.

We have changed where we were using “esthesiometry” to SWM-test in all manuscript. Also, we have changed the using of the adjective “Esthesiometric” to SMW-test preceding the nouns throughout the paper marked in red writing.

Initially, in lines 99-100, we excluded the sentence “also known as an esthesiometer” becoming: “Semmes-Weinstein monofilaments (SWM) are used to assess and monitor tactile sensation in specific territories of the nerve trunks of the hands and feet.”

In other important point, in Methods (page 6 – lines 153-154) we changed the subtitle Esthesiometry for “Tactile sensation test by Semmes-Weinstein Monofilaments (SWM-test)” to emphasize the correct meaning according to your suggestions (thanks again).

2. Abstract: This sensation is an example of how difficult it is to express what the authors are trying to say. They state “a 18% improvement in tactile sensitivity for the hands, and 28.7% for the feet was detected.” What can this possibly mean. Do they mean that 18% of their total number of hand patients had an improvement in sensation, or do they mean that the pre-treatment mean measurement has improved 18% for the hand.

Author’s comments: Thanks for bring us your difficulty to understanding our test. We are sure they will become our work better. In the abstract we changed this part for:

“At diagnosis, 81/107 (75.7%) patients had some degree of functional disability, and 46 (43%) of them had altered SWM-test in the hands and 94 (87.9%) of them in the feet. After one year of multibacillary multidrug therapy, the disability decreasing to 44/76 patients (57.9%) and decreasing of the percentual of altered SWM-test to 18% for the hands, and to 28.7% for the feet.”

Also, in the summary we have changed these considerations (marked in yellow):

“At diagnosis, 43% of them had altered SWM-test in the hands, while 87.9% had it in the feet. After one year of multibacillary multidrug therapy, the percentual of patients with altered SWM-test decreased to 18% for the hands and 28.7% for the feet.

3. Abstract: the next line is very confusing also: “In the hands, by esthesiometry, radial nerve was significantly asymmetric, while in the feet, the difference between the sum of altered esthesiometric points showed significant asymmetry when comparing both sides, highlighting the tibial nerve for the establishment of asymmetric leprosy neuropathy.” Can even the authors understand what this means????

Author’s comments: Thanks for your comment. We changed the test to be clearer and more understandable.

“In the hands, by SWM-test, only the radial nerve point demonstrated a significant asymmetry, while in the feet, the difference between the sum of altered SWM-test points showed significant asymmetry between both sides, highlighting the tibial nerve for the establishment of asymmetric leprosy neuropathy.”

4. The word “sensitivity” is still in this manuscript. Sensitivity is a statistical term as in sensitivity versus specificity. They use it wrongly when they should be saying sensibility.

Author’s comments: We understand your question, but we must disagree about your statement, as the term SENSITIVITY is not exclusive to statistics. According to several works in neuropathy, including some of our group, we have published it as SENSITIVITY, although some reviewers suggest that we change to "sensation", much more frequent than SENSIBILITY.

1. Frade MAC, Rosa DJF, Bernardes-Filho F, Spencer JS, Foss NT. Semmes-Weinstein monofila-ment: A tool to quantify skin sensation in macular lesions for leprosy diagnosis. Indian J Der-matol Venereol Leprol 2021; XX:1-9. (Added in our reference)

2. Fernanda Guzzo Gomes, Wilson Marques, Norma Tiraboschi Foss, Luísiane de Ávila Santana, Marco Andrey Cipriani Frade. Tactile threshold detection in leprosy patients with an electronic algometer. Journal of Neuroscience Methods, Volume 179, Issue 2, 2009, Pages 319-322,ISSN 0165-0270, https://doi.org/10.1016/j.jneumeth.2009.01.030.

3. Pedro J Tomaselli, Diogo F dos Santos, André C J dos Santos, Douglas E Antunes, Vanessa D Marques, Norma T Foss, Carolina L Moreira, Patrícia T B Nogueira, Osvaldo J M Nascimento, Luciano Neder, Amilton A Barreira, Marco A Frade, Isabela M B Goulart, Wilson Marques, Jr, Primary neural leprosy: clinical, neurophysiological and pathological presentation and pro-gression, Brain, 2021;, awab396, https://doi.org/10.1093/brain/awab396 (published in Octo-ber 2021)

5. Conclusion: Sadly ,the authors FAIL to discus that the remaining disability these patients have is due to chronic nerve compression, which can be helped by surgical decompression. They must emphasize that while the r value of .80 is great after triple drug therapy, r2 = 64 which means that 36% of meaning is unexplained or not improved. Those patients after triple drug therapy have residual disability that appropriate peripheral nerve surgery can help. References to this fact were added as refs 34 and 35 at the very last lines of the Discussion, however only to say that drug therapy can reduce the need for surgery, rather than adding the remaining patients would benefit from surgery, and this needs to be emphasized.

a) Wan, EL, Rivadeniera, AF, Jousin, RM, Dellon, AL, Treatment of Peripheral Neuropathy in Leprosy: The case for nerve decompression, Plast Reconstr Surg GO, 2016; 4:e637; doi10.1097/GO0000000000000641.

b) b) Wan, E, Rivadeniera, AF, Serrano, HA, Napit, I, Garbino, JA, Joshua, J, Cardona-Castro, N, Dellon, AL, Theuvenet, W, Protocol for a randomized controlled trial investigating decompression for leprous neuropathy (the DELN protocol), Lepr Rev, 87:553-561, 2016.

Author’s comments: Thanks for your comment. We would like to say that now we understand you and we changed the last paragraph of the DISCUSSION to consider your point. In our conclusion, we considered difficult to include it because we did not consider this surgery procedure in our assistance unfortunately.

Lines 634-42: ….“It is worth emphasizing that those patients who, even after multidrug therapy, still have residual disability detected by the SWM test, may benefit from appropriate peripheral nerve decompression surgery, preventing definitive neural damage from leprosy, as described by Wan et al [34,35].”

Specifically in conclusion, we changed the writing explaining better about the SWM-test as a tactile sensitivity test:

Line 648 – “The tactile sensation test using Semmes-Weisntein monofilaments proved to be an important instrument…”

Line 673 – “Finally, hand and foot tactile sensation test using Semmes-Weinstein monofilaments proved to be effective…”

Additionally, we received recently (after our submission to the journal) one communication from the Brazilian health Ministry together SORRI, the company that produces the monofilament kits in Brazil about the change of the green monofilament from 0.05g to 0.07g recently adopted the new kit manual. According to the document below signed by Mr. Antony R. J. Nicholl, owner of the company with large expertise in SWM (we have made a free translation for English language), and considering that all our calculations were made considering values greater than 0.05 and as there is no value between 0.05 and 0.07, it has not really changed in our results and analysis, so we decided to do this up to date in our manuscript changing from 0.5 g-force to 0.07 g-force.

In the manuscript we changed it in lines: 123, 136, 151, 159, 162, 167, 172, 180, 200 (Table 1), 255, 271, 290 and 495.

Thank you very much for these so important contributions!

Submitted filename: Author Responses JAN 22, 2022.docx

Click here for additional data file.

14 Jul 2022

Evaluation of altered patterns of tactile sensation in the diagnosis and monitoring of leprosy using the Semmes-Weinstein monofilaments

PONE-D-21-17910R2

Dear Dr. Frade,

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2 Aug 2022

PONE-D-21-17910R2

Evaluation of altered patterns of tactile sensation in the diagnosis and monitoring of leprosy using the Semmes-Weinstein monofilaments

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Table 8

Distribution of the number of SWM-test (normal and altered) points of the hands per patient at the end of the treatment and corresponding nerves.

	Median nerve (Points: 1, 2, 3)				Ulnar nerve (Points 4, 5, 6)				Radial nerve (Point 7)
	R		L		R		L		R		L
	n	%	n	%	n	%	n	%	n	%	n	%
No altered point	61	80.3	64	84.2	61	80.3	63	82.9	65	85.5	63	82.9
1 altered point	3	3.9	2	2.6	5	6.6	0	0	11	14.5	13	17.1
2 altered points	1	2.3	2	2.6	3	3.9	2	2.6	-	-	-	-
3 altered points	11	14.5	8	10.5	7	9.2	11	14.5	-	-	-	-
Total	76	100	76	100	76	100	76	100	76	100	76	100

n: number; %: percentage; R: right; L: left.

Table 9

Distribution of the number of SWM-test (normal and altered) points of the feet per patient at the treatment diagnosis and corresponding nerves.

	Medial plantar branch (Points 1, 2, 4, 5, 7)				Lateral plantar branch (Points 3, 6)				Sural nerve (Point 8)				Calcaneal branch (Point 9)
	R		L		R		L		R		L		R		L
	n	%	n	%	n	%	N	%	n	%	n	%	n	%	n	%
No altered point	44	41.1	41	38.3	54	50.5	44	41.1	49	45.8	54	50.5	21	19.6	21	19.6
1 altered point	14	13.1	10	9.3	24	22.4	26	24.3	58	54.2	53	49.5	86	80.4	86	80.4
2 altered points	13	12.1	16	15.0	29	27.1	37	34.6	-	-	-	-	-	-	-	-
3 altered points	11	10.3	12	11.2	-	-	-	-	-	-	-	-	-	-	-	-
4 altered points	8	7.5	9	8.4	-	-	-	-	-	-	-	-	-	-	-	-
5 altered points	17	15.9	19	17.8	-	-	-	-	-	-	-	-	-	-	-	-
Total	107	100	107	100	107	100	107	100	107	100	107	100	107	100	107	100

n: number; %: percentage; R: right; L: left.