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Botulinum Toxin Type B Blocks Sudomotor Function Effectively: A 6 Month Follow Up

2003; Elsevier BV; Volume: 121; Issue: 6 Linguagem: Inglês

10.1046/j.1523-1747.2003.12620.x

1523-1747

Frank Birklein, Gabi Eisenbarth, Frank Erbguth, Martin Winterholler,

Myofascial pain diagnosis and treatment

This study analyzes the suppression of sweat gland activity by botulinum toxin type B. We injected botulinum toxin type B (between 2 and 1000 mouse units subcutaneously) in the lateral side of both lower legs in 15 healthy volunteers. Sweat tests were carried out before botulinum toxin type B injections, and at 3 wk, 3 mo, and 6 mo. We studied focal anhidrosis by iodine–starch staining and by capacitance hygrometry after carbachol iontophoresis, according to the quantitative sudomotor axon reflex test (QSART). Iodine starch staining indicated that a threshold dose of 8 mouse units botulinum toxin type B leads to anhidrotic skin spots (>4 cm2) after 3 wk. Duration of anhidrosis was prolonged for 3 mo when 15 mouse units and for 6 mo when 125 mouse units botulinum toxin type B were injected. The size of the anhidrotic area decreased with time (p 4 cm2) after 3 wk. Duration of anhidrosis was prolonged for 3 mo when 15 mouse units and for 6 mo when 125 mouse units botulinum toxin type B were injected. The size of the anhidrotic area decreased with time (p<0.001), indicating partial recovery at the edges. After 3 wk, the QSART score had significantly decreased to 18% of baseline and had decreased to zero in most subjects with doses of 62.5 mouse units or more. After 3 mo, the QSART had returned to 91% of baseline in all but one subject and, after 6 mo, recovery of sudomotor function was complete. Analysis by iodine–starch staining and QSART indicated that botulinum toxin type B suppresses sudomotor function effectively, in a concentration-dependent manner. The family of botulinum toxins includes seven clostridial neurotoxins (types A–G), which block neuromuscular transmission. Botulinum toxin type A (BoNT/A) was used effectively to treat a range of movement disorders (Jankovic and Schwartz, 1993Jankovic J. Schwartz K.S. Longitudinal experience with botulinum toxin injections for treatment of blepharospasm and cervical dystonia.Neurology. 1993; 43: 834-836Crossref PubMed Google Scholar). BoNT/A also blocks autonomic nerve function and is effective in focal hyperhidrosis and hypersalivation (Heckmann et al., 2001Heckmann M. Ceballos-Baumann A.O. Plewig G. Botulinum toxin A for axillary hyperhidrosis (excessive sweating).N Engl J Med. 2001; 344: 488-493Crossref PubMed Scopus (339) Google Scholar). Recently, Botulinum toxin type B (BoNT/B) has been approved for the treatment of cervical dystonias (Lew et al., 2000Lew M.F. Brashear A. Factor S. The safety and efficacy of botulinum toxin type B in the treatment of patients with cervical dystoni: Summary of three controlled clinical trials.Neurology. 2000; 55: S29-S35PubMed Google Scholar). Both BoNT/A and BoNT/B are di-chain proteins of heavy and light chains that act preferentially in cholinergic nerves. Heavy chains determine neuron-specific binding. Light chains act intracellularly to inactivate the fusion protein complex, which is necessary for the exocytosis of acetylcholine. Botulinum toxins therefore block neuromuscular transmission, causing muscle weakness and atrophy. For BoNT/A, intracellular degradation is slow and it therefore takes 3 to 4 mo before muscle weakness is reversed (Zimmermann, 1996Zimmermann H. Molekulare Funktionsträger der Nervenzelle.in: Dudel J. Menzel R. Schmidt R.F. Neurowisenschaft: Vom Molekül Zur Kognition. Berlin, Berlinw1996: 33-61Google Scholar). For other toxin types, intracellular degradation is faster or they have different intracellular targets than BoNT/A. Therefore, the effects of BoNT/A and BoNT/B in humans differ. Clinical and in vivo studies have shown that BoNT/A is 20 to 50 times more effective in blocking neuromuscular transmission than BoNT/B (Sloop et al., 1997Sloop R.R. Cole B.A. Escutin R.O. Human response to botulinum toxin injection: Type B compared with type A.Neurology. 1997; 49: 189-194Crossref PubMed Scopus (160) Google Scholar). For the treatment of spasmodic torticollis, BoNT/A is used at 100 or 500 (depending on the preparation) lethal mouse doses (mouse units, MU), whereas BoNT/B is required at 5000 to 10,000 mu. Treating patients with spasmodic torticollis with BoNT/B, however, frequently causes autonomic side-effects, such as hyposalivation, accommodation paresis, or reduction of respiratory heart rate variation. These autonomic side-effects may point to a potential value of BoNT/B for the treatment of hyperhidrosis. Recently, we presented a study quantifying the inhibitory effects of BoNT/A on sudomotor function in humans (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). We found a concentration-dependent reduction in sweat gland activity, with a minimal dose of 10 mu BoNT/A (Dysport, Ipsen Pharma, Maidenhead, UK) required to induce reproducibly focal anhidrosis after subcutaneous injection in healthy subjects. With doses higher than 50 mu anhidrosis was maintained for 6 mo. No quantitative data are available for the inhibitory effects of BoNT/B on sudomotor nerves. We sought to obtain data for comparison of BoNT/A and BoNT/B. Therefore we employed an identical protocol as described in a previous study (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). We thereby intended to analyze the role of BoNT/B in future treatment strategies for focal hyperhidrosis. We examined sudomotor function in 15 healthy volunteers (nine men, six women) before and at 3 wk, 3 mo, and 6 mo after subcutaneous injections of BoNT/B. All participants were injected on both legs (30 legs) with different doses. We used a commercially available preparation of BoNT/B (NeuroBloc, Elan Pharmaceuticals, Dublin, Ireland) with an original concentration of 5000 U per mL. The toxin doses ranging from 2 to 1000 mu (Table I) were diluted in 1 mL of isotonic saline to yield constant volumes. BoNT/B was injected subcutaneously, using a 27 G needle, at the lateral aspects of calves midway between the fibular head and the lateral malleolus. In accordance with the ring-shaped sweat capsule (2.5 cm diameter) of the quantitative sudomotor axon reflex test (QSART) device (below), we used a fixed injection scheme with four injections (square, distance 2 cm). We determined the area of focal anhidrosis and measured sudomotor function. The local ethics committee of the University of Erlangen approved the study and all participants gave written informed consent.Table IThe table shows individual results of QSART and the corresponding area of anhidrotic skin. Doses of BoNT/B sufficient to suppress QSART completely or to induce focal anhidrosis safely at different time points are indicated by bold typeQSART % of baseline sessionArea of anhidrosis in cm2BoNT/B in MU3 wk after injection3 mo after injection6 mo after injection3 wk after injection3 mo after injection6 mo after injection10000%10%149%120501010000%0%121%524614100022%55%172%5352225004%123%104%843905000%73%120%603665000%50%170%3641192509%75%199%4332152500%19%46%4827102500%37%158%4230161250%89%82%3023812514%111%176%241801250%42%92%322817630%111%81%30140630%23%114%361206357%193%125%271003111%116%128%261203123%44%MissingaSubject refused to participate in QSART a third time.241003129%43%97%241201568%124%141%1840150%138%MissingaSubject refused to participate in QSART a third time.23601543%91%74%1840893%182%–bQSART was not performed as it has already normalized after 3 mo with low doses.10408102%126%–bQSART was not performed as it has already normalized after 3 mo with low doses.500863%81%–bQSART was not performed as it has already normalized after 3 mo with low doses.700440%92%–bQSART was not performed as it has already normalized after 3 mo with low doses.7004152%162%–bQSART was not performed as it has already normalized after 3 mo with low doses.0004103%111%–bQSART was not performed as it has already normalized after 3 mo with low doses.000258%96%–bQSART was not performed as it has already normalized after 3 mo with low doses.0002132%119%–bQSART was not performed as it has already normalized after 3 mo with low doses.0002136%161%–bQSART was not performed as it has already normalized after 3 mo with low doses.400a Subject refused to participate in QSART a third time.b QSART was not performed as it has already normalized after 3 mo with low doses. Open table in a new tab The patients were acclimatized in a temperature-controlled and humidity controlled laboratory. Sweating was induced by infra-red irradiation and hot tea (Birklein and Erbguth, 2000Birklein F. Erbguth F. Sudomotor testing discriminates between subjects with and without antibodies against botulinum toxin A—A preliminary observation.Mov Disord. 2000; 15: 146-149Crossref PubMed Scopus (16) Google Scholar). To identify the area of anhidrotic skin after BoNT/B injection, we used iodine–starch staining (Minor, 1927Minor V. Ein Neues Verfahren zu der klinischen Untersuchung der Schweissabsonderung.Z Neurol. 1927; 101: 302-308Crossref Scopus (230) Google Scholar). Skin that retained sudomotor function changed from white to dark blue, whereas the anhidrotic skin remained white. To measure the area of anhidrosis, we took photographs of both legs with a red–green–blue camera (Cohu 8312, single charge-coupled device, Cohu, Inc. San Diego, California), and the pictures were digitized by frame-grabber software (Oculus TCX 2; Coreco, St Laurent, Quebec, Canada). For calibration, we marked the corners of an area of 10 cm2 on each photo (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). Transcutaneous iontophoresis (1 mA, 5 min) of 1% carbachol directly activated sweat glands via muscarinic acetylcholine receptors at the stimulation site, and induced sudomotor axon reflex sweating via nicotinic acetylcholine receptors on sudomotor axons in the vicinity (Riedl et al., 1998Riedl B. Nischik M. Birklein F. Neundörfer B. Handwerker H.O. Spatial extension of sudomotor axon reflex sweating in human skin.J Auton Nerv Syst. 1998; 69: 83-88Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). In order to assess the axon reflex sweating, we placed a sweat chamber (covering 5 cm2 of skin) on those areas of the lower legs that, at later time points, had been pretreated with BoNT/B. The respective skin areas were identified in each subject by landmarks or by iodine–starch staining, which was performed before. Our sweat chambers were constructed to consist of two separate compartments: One in the middle (the stimulation compartment) for the iontophoreses electrode where "muscarinic sweating" occurs, and a circular one around (the measuring compartment), which covers the nicotinergic sudomotor axon reflex skin area (QSART) (Lang et al., 1993Lang E. Foerster A. Pfannmüller D. Handwerker H.O. Quantitative assessment of sudomotor activity by capacitance hygrometry.Clin Auton Res. 1993; 3: 107-115Crossref PubMed Scopus (46) Google Scholar). The ability to assess exclusively the axon reflex sweating with this method has been demonstrated before by complete suppression of sweating using local anesthetics (Low et al., 1983Low P.A. Caskey P.E. Tuck R.R. Fealey R.D. Dyck P.J. Quantitative sudomotor axon reflex test in normal and neuropathic subjects.Ann Neurol. 1983; 14: 573-580Crossref PubMed Scopus (437) Google Scholar). For the quantification of sweating, dry nitrogen gas (relative humidity <5%) was passed through the sweat chambers at a constant flow (270 mL per min) causing evaporation. Relative humidity was measured by capacitance hygrometers (Rotronic AG, Basel, Switzerland), their output was digitized and stored in a PC for further analysis. QSART was not performed at 6 mo in those subjects in whom sweating had already normalized after 3 mo. First, baseline sweating was recorded for 2 min in each session, then iontophoreses was started, and sweating was recorded for a further 15 min. To calculate axon reflex sweating, the baseline (mean values of the first 2 min) was subtracted from the original curve, and the area under this difference curve (AUC) was plotted as an integral function. The volume of stimulus-evoked sweating was quantified by computing AUC for 10 min following iontophoreses (Birklein et al., 1997Birklein F. Sittl R. Spitzer A. Claus D. Neundörfer B. Handwerker H.O. Sudomotor function in sympathetic reflex dystrophy.Pain. 1997; 69: 49-54Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar). As QSART is known to vary between individuals (e.g., between men and women;Low et al., 1983Low P.A. Caskey P.E. Tuck R.R. Fealey R.D. Dyck P.J. Quantitative sudomotor axon reflex test in normal and neuropathic subjects.Ann Neurol. 1983; 14: 573-580Crossref PubMed Scopus (437) Google Scholar), results were expressed as percent change of individual baseline values. Significant differences in results obtained from different sessions were identified by Wilcoxon's matched pairs signed rank test, corrected for multiple comparisons. Correlations between different variables were determined by the Spearman rho correlation coefficient. As normal distribution could not be assumed in our datasets, nonparametric statistics were calculated. Accordingly, all values are given as median and interquartile ranges. p-values less than 0.05 were considered significant. Statistical analysis was performed using the SPSS software package (SPSS Inc., Chicago, Illinois). As all subjects had no sweating abnormalities, iodine–starch staining was not performed before BoNT/B injection. If doses of 8 mu BoNT/B or more were injected, iodine–starch staining 3 wk after BoNT/B injection revealed an anhidrotic skin spot (24.9 cm2; range 6.7–42.0 cm2) (Table I). After 3 mo, the area of anhidrotic skin decreased (11.7 cm2; 0–30.2), but anhidrosis was still present if more than 15 mu BoNT/B had been injected previously. After 6 mo, the area of anhidrotic skin further decreased (0 cm2; 0–10.0, Friedman χ2=48.1, p<0.001). With the exception of two subjects, however, an anhidrotic skin spot remained if 125 mu or more BoNT/B had been injected. Differences between 3 wk, 3 mo, and 6 mo were significant (Wilcoxon, p<0.001 each), suggesting successful recovery of sweat gland function (Table I, Figure 1). The area of anhidrotic skin was BoNT/B concentration dependent at 3 wk (rho=+0.97, p<0.001), 3 mo (rho=+0.98, p<0.001), and 6 mo after injection (rho=+0.75; p<0.001) (Figure 2). This was performed in all subjects in a session before BoNT/B injection to provide baseline values. As there is no difference between right and left legs in healthy subjects (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar;Birklein et al., 2002Birklein F. Walther D. Bigalke H. Winterholler M. Erbguth F. Sudomotor testing predicts the presence of neutralizing botulinum A toxin antibodies.Ann Neurol. 2002; 52: 68-73Crossref PubMed Scopus (13) Google Scholar), we pooled measurements for both legs (AUC of 534 arbitrary units; range 379–744). After 3 wk, QSART was reduced to 18% of baseline (range 0–64) and even absent in 10 of 15 subjects with BoNT/B doses of 62.5 mu or more (Table I). After 3 mo, QSART had almost returned to baseline (91% of baseline; range 44–123) in all but one subject. After 6 mo, QSART scores had returned to baseline or even exceeded baseline (123%; range 93–156, Friedman χ2=27.4, p<0.001). The recovery in sudomotor function observed with the QSART between 3 wk and 3 mo was significant (Wilcoxon, p<0.001; Table I). Similar to iodine–starch staining, suppression of sweating in the QSART was BoNT/B concentration dependent. This concentration dependence was shown in a significant negative correlation between QSART and BoNT/B doses after 3 wk (rho=–0.79; p<0.001) and after 3 mo (rho=–0.61, p<0.001): QSART scores were higher with lower doses of BoNT/B and lower with higher doses (Figure 3). After 6 mo, the correlation became positive, although it was then no longer significant (rho=+0.36, not significant). Three weeks after BoNT/B injection, there was a significant negative correlation between QSART and the anhidrotic skin area (rho=–0.83; p<0.001), which was weaker but still present after 3 mo (rho=–0.60, p<0.001). After 6 mo there was positive correlation between QSART and anhidrotic skin area (rho=+0.57, p<0.01). Anhidrosis was maintained for 3 wk after administration of doses of 8 mu BoNT/B per 4 cm2 skin. Anhidrosis was maintained for 3 mo if 15 mu BoNT/B per 4 cm2 were injected. Accordingly, when BoNT/B dose and area of anhidrotic skin were plotted, the slope of the line of regression at lower dose ranges was 0.49 after 3 wk and 0.21 after 3 mo. In other words, we had to inject 2 mu per cm2 to ensure a reduction in local sweat gland activity, which could be maintained for 3 mo if 4 or 5 mu per cm2 were used. Anhidrotic skin could be detected even after 6 mo if 125 mu per 4 cm2 (about 30 mu per cm2) had been injected previously; however, anhidrosis was then no longer concentration dependent (Figure 2). No subject reported any serious side-effects. Even the highest doses of BoNT/B (1000 mu) induced neither permanent nor transient weakness of underlying muscles. No distant autonomic side-effects, such as dry mouth or eyes, were reported. This study revealed that BoNT/B blocks sweating after subcutaneous application in a concentration-dependent manner. This anhidrosis was not transient; it could be maintained for 3 mo with small doses and for 6 mo with larger doses. As very large doses are usually required to block motor neurons, BoNT/B is much more effective in blocking sudomotor nerves than motor neurons in humans. There are obvious differences between BoNT/A and BoNT/B efficacy in inhibiting motor function in humans (Brin et al., 1999Brin M.F. Lew M.F. Dykstra D.D. et al.Safety and efficacy of NeuroBloc (botulinum toxin type B) in type A-responsive cervical dystonia.Neurology. 1999; 53: 1439-1446Crossref PubMed Google Scholar). BoNT/A (Dysport, Ipsen Pharma) is between 20 and 50 times more potent in treating spasmodic torticollis in humans than BoNT/B (NeuroBloc, Elan Pharmaceuticals), as measured in lethal mouse doses. In a previous investigation, employing the same investigation protocol as presented here, we have shown that a minimum dose of 10 mu BoNT/A (Dysport) causes a local anhidrotic skin patch and 80 mu abolishes sweat gland activity, measured by QSART, after 3 wk. A minimum dose of 50 mu BoNT/A was effective to maintain focal anhidrosis for 6 mo, but QSART recovered in all subjects, even if 120 mu had been injected (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). This study shows that BoNT/B is comparably effective as BoNT/A in blocking sudomotor function for 3 mo. Slightly higher doses of BoNT/B (125 mu) than BoNT/A (50 mu, Dysport) were needed to maintain anhidrosis for 6 mo, indicating that recovery of sudomotor function is better with BoNT/B. This shorter-lasting effect of BoNT/B is in accordance with previous investigations of motor recovery (Hanna and Jankovic, 1998Hanna P.A. Jankovic J. Mouse bioassay versus Western blot assay for botulinum toxin antibodies: Correlation with clinical response.Neurology. 1998; 50: 1624-1629Crossref PubMed Scopus (107) Google Scholar). The higher affinity of BoNT/B for the sudomotor nerve than for the motor neuron has two effects: autonomic side-effects are observed more frequently with BoNT/B therapy of muscular hypercontractions than with BoNT/A because the high doses of BoNT/B required to affect motor function influence the autonomic nervous system and lead to distant side-effects. On the other hand, however, when BoNT/B is injected to treat hyperhidrosis in sensitive skin areas such as palms or soles, muscle weakness is unlikely to be a side-effect. The molecular reasons why BoNT/B preferentially blocks autonomic nerves remain unclear. Toxin type-specific binding of toxin heavy chains to different cholinergic nerves may play a part (Brin, 1997Brin M.F. Botulinum toxin: Chemistry, pharmacology, toxicity, and immunology.Muscle Nerve. 1997; 6: S146-S168Crossref PubMed Google Scholar), or the intracellular target of BoNT/B, synaptobrevin, may have different importance for exocytosis in motor and sudomotor nerves (Lalli et al., 1999Lalli G. Herreros J. Osborne S.L. Montecucco C. Rossetto O. Schiavo G. Functional characterisation of tetanus and botulinum neurotoxins binding domains.J Cell Sci. 1999; 112: 2715-2724PubMed Google Scholar). This study suggests that in motor nerves synaptobrevin is restored more effectively than SNAP25, the intracellular target of BoNT/A. From this study, one can calculate that BoNT/B at a dose of 5 mu per cm2 must be injected every 3 mo to maintain anhidrosis. For example, if axillary hyperhidrosis occurs in an area of 100 cm2, repeated injections of 500 mu BoNT/B should maintain anhidrosis permanently. We investigated only healthy subjects, as in our BoNT/A study (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). As sweat glands and sudomotor nerves do not substantially change their functional properties in hyperhidrosis, there is no physiologic reason to doubt that similar results would be obtained in hyperhidrosis patients. Nevertheless, therapy studies in hyperhidrosis are needed to establish effective doses of BoNT/B. For dose finding there is a further source of variability. We diluted all doses of BoNT/B in saline to yield constant volumes. BoNT/B, however, shows some unspecific binding to glass or plastic surfaces. That is why BoNT/B is delivered with albumin. By diluting BoNT/B we also diluted albumin. In the very low-dose range albumin should be too low to prevent further some unspecific BoNT/B binding. Therefore, sudomotor blocking effects of BoNT/B in this study might even be underestimated, in particular in low doses. Focal suppression of sweating starts 1 d after subcutaneous injection of BoNT/A and the size of the anhidrotic skin spot increases to a maximum 1 to 2 wk later (Krämer et al., 2003Krämer H.H. Angerer C. Erbguth F. Schmelz M. Birklein F. Botulinum Toxin A. Reduces neurogenic flare but has almost no effect on cutaneous pain and hyperalgesia in humans.J Neurol. 2003; 250: 188-193Crossref PubMed Scopus (82) Google Scholar). In this study, we chose investigation time points of 3 wk, 3 mo, and 6 mo because recovery of sweat function occurs during this time (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). We measured sweat production in two ways: iodine–starch staining indicates clinically relevant impairment of sweating, and QSART provides quantitative information on BoNT/B efficacy (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). Results obtained with both methods were highly correlated and demonstrated a concentration-dependent reduction of sweating after BoNT/B injection. Iodine–starch staining is an easy bedside test and is sensitive enough to visualize even small areas of anhidrosis. QSART requires a more complex experimental set-up (Lang et al., 1993Lang E. Foerster A. Pfannmüller D. Handwerker H.O. Quantitative assessment of sudomotor activity by capacitance hygrometry.Clin Auton Res. 1993; 3: 107-115Crossref PubMed Scopus (46) Google Scholar), and iontophoresis of carbachol is obviously a more intense stimulus than physiologic activation of sweat glands. The difference in stimuli may be the major reason for different results, particularly with lower BoNT/B doses. Interestingly, the QSART score was occasionally above baseline values in the low-dose range. This is similar to a previous study on BoNT/A (Braune et al., 2001Braune C. Erbguth F. Birklein F. Dose thresholds and duration of the local anhidrotic effect of botulinum toxin injections: Measured by sudometry.Br J Dermatol. 2001; 144: 111-117Crossref PubMed Scopus (43) Google Scholar). This phenomenon may be related to a so-called "perilesional hyperhidrosis" (Low and Kennedy, 1997Low P.A. Kennedy W.R. Cutaneous effectors as indicators of abnormal sympathetic function.in: Morris J.L. Gibbins I.J. Autonomic Innervation of the Skin. Harwood Academic Publishers, Amsterdam1997: 165-212Google Scholar) and may also explain increased QSART responses observed in very early cases of polyneuropathy (Low et al., 1983Low P.A. Caskey P.E. Tuck R.R. Fealey R.D. Dyck P.J. Quantitative sudomotor axon reflex test in normal and neuropathic subjects.Ann Neurol. 1983; 14: 573-580Crossref PubMed Scopus (437) Google Scholar). In conclusion, our results suggest a promising role of BoNT/B in future therapies for focal hyperhidrosis. If our results are replicated in patients, BoNT/B could become the therapy of choice, and replace BoNT/A in hyperhidrosis therapy.