• View in gallery
    Figure 1—

    Sagittal T1-weighted spin echo image of the foot of a representative horse with degenerative injury to the PA after injection of the NB with BTXB. Notice the large erosion of the flexor cortex of the navicular bone. The navicular bone has a defect in the flexor cortex with a high signal intensity (large white arrow), and there is an area of low to intermediate signal intensity within the medullary cavity (small white arrow). There is also loss of definition of the dorsal aspect of the deep digital flexor tendon and thickening of the CSL (black arrow).

  • View in gallery
    Figure 2—

    Box-and-whisker plots of lameness scores for the treated forelimb in horses with degenerative injury to the PA of both forelimbs that had the limb with the most severe lameness treated by injection of BTXB into the podotrochlear bursa (NB). Lameness scores were assigned for horses when they trotted in a straight line (A), in a circle with the treated limb to the inside of the circle (B), and in a circle with the treated limb to the outside of the circle (C) at each of 3 time points (baseline [5 days before BXTB administration] and 7 and 14 days after BTXB administration). Lameness scores were determined separately by 3 investigators from video recordings; lameness was scored from 0 to 5 by use of a scale modified from the American Association of Equine Practitioners’ lameness grading scale. Results represent data for 7 horses at baseline and day 7 and 6 horses at day 14 because 1 horse was removed from the study on day 8 at the owner's request. Each box represents the interquartile range (25th to 75th percentiles), the horizontal line in each box represents the median, the whiskers represent 1.5 times the interquartile range, and circles represent values > 1.5 times the interquartile range. a,bWithin each panel, time points with different letters differ significantly (P ≤ 0.05).

  • View in gallery
    Figure 3—

    Box-and-whisker plots of lameness scores for the contralateral untreated forelimb in horses with degenerative injury to the PA of both forelimbs that had the limb with the most severe lameness treated by injection of BTXB into the NB. Within each panel, lameness grades did not differ significantly (P = 0.71) among time points. See Figure 2 for remainder of key.

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Effects of intrabursal administration of botulinum toxin type B on lameness in horses with degenerative injury to the podotrochlear apparatus

Santiago D. Gutierrez-NibeyroDepartment of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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Marcos P. SantosDepartment of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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Nathaniel A. White IIMarion duPont Scott Equine Medical Center, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Leesburg, VA 20177.

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James A. BrownMarion duPont Scott Equine Medical Center, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Leesburg, VA 20177.

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M. Norris AdamsMarion duPont Scott Equine Medical Center, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Leesburg, VA 20177.

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Alexia L. McKnightMcKnight Insight LLC, 258 Heyburn Rd, Chadds Ford, PA 19317.

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David J. SchaefferDepartment of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana, IL 61802.

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Abstract

Objective—To determine the safety and short-term efficacy of intrabursal administration of botulinum toxin type B (BTXB) to alleviate lameness in horses with degenerative injury to the podotrochlear apparatus (PA).

Animals—10 Quarter Horses with degenerative injury to the PA.

Procedures—Degenerative injury to the PA was confirmed with diagnostic analgesia and imaging. Then, BTXB (3.8 to 4.5 U/kg) was injected into the podotrochlear (navicular) bursa of each horse. Three horses were used in a safety evaluation. Subsequently, video recordings of lameness evaluations were obtained for 7 client-owned horses 5 days before (baseline) and 7 and 14 days after BTXB treatment and used to determine the effect of BTXB injection on lameness; 1 horse was removed from the study 8 days after BTXB treatment. Three investigators who were unaware of the treated forelimbs or time points separately reviewed the recordings and graded the lameness of both forelimbs of the horses.

Results—Improvement in lameness of the treated forelimbs was detected at 1 or both time points after BTXB administration in all horses. However, all horses had some degree of lameness at the end of the study. Two horses developed transient increases in lameness 48 to 72 hours after treatment; lameness resolved uneventfully.

Conclusions and Clinical Relevance—Intrabursal injection of BTXB temporarily alleviated chronic lameness in horses with degenerative injury to the PA, without causing serious short-term adverse effects. Further investigation into the potential use of BTXB in horses affected by degenerative injury to the PA is warranted.

Abstract

Objective—To determine the safety and short-term efficacy of intrabursal administration of botulinum toxin type B (BTXB) to alleviate lameness in horses with degenerative injury to the podotrochlear apparatus (PA).

Animals—10 Quarter Horses with degenerative injury to the PA.

Procedures—Degenerative injury to the PA was confirmed with diagnostic analgesia and imaging. Then, BTXB (3.8 to 4.5 U/kg) was injected into the podotrochlear (navicular) bursa of each horse. Three horses were used in a safety evaluation. Subsequently, video recordings of lameness evaluations were obtained for 7 client-owned horses 5 days before (baseline) and 7 and 14 days after BTXB treatment and used to determine the effect of BTXB injection on lameness; 1 horse was removed from the study 8 days after BTXB treatment. Three investigators who were unaware of the treated forelimbs or time points separately reviewed the recordings and graded the lameness of both forelimbs of the horses.

Results—Improvement in lameness of the treated forelimbs was detected at 1 or both time points after BTXB administration in all horses. However, all horses had some degree of lameness at the end of the study. Two horses developed transient increases in lameness 48 to 72 hours after treatment; lameness resolved uneventfully.

Conclusions and Clinical Relevance—Intrabursal injection of BTXB temporarily alleviated chronic lameness in horses with degenerative injury to the PA, without causing serious short-term adverse effects. Further investigation into the potential use of BTXB in horses affected by degenerative injury to the PA is warranted.

Degenerative injury to the PA in horses causes chronic forelimb lameness because of pain arising from the navicular bone and soft tissues of the PA, such as the CSLs, distal sesamoidean impar ligament, podotrochlear bursa (ie, NB), and deep digital flexor tendon.1–5 The PA is innervated by unmyelinated sensory fibers that contain SP, CGRP, and other neuropeptides.6–8 Investigators have detected a high density of unmyelinated nerve fibers in the CSLs and distal sesamoidean impar ligament and a lower density of unmyelinated nerve fibers in the navicular bone and deep digital flexor tendon.6,7 Therefore, it is speculated that these nerve fibers mediate transmission of foot pain to the spinal cord in horses with degenerative injury to the PA.9 In fact, investigators in 1 study2 found nerve fibers with more immunostaining for SP and CGRP in the CSLs of horses with degenerative injury of the PA, compared with immunostaining in the CSLs of horses with no signs of foot pain. This information suggests that medications capable of modulating neuropeptide release within the PA may have a role in the treatment of degenerative injury to the PA.

Botulinum toxins are used to treat humans with muscle spasticity.10 However, antinociceptive effects after botulinum toxin injections have been reported in clinical trials of patients with cervical dystonia,11 lateral epicondylitis,12 plantar fasciitis,13 and osteoarthritis of the shoulder joint.14 The analgesic effects observed clinically have been confirmed in mice,15,16 rats,17 and dogs18 with experimentally induced and naturally occurring inflammation. Moreover, botulinum toxins can inhibit the release from peripheral sensory neurons of neuropeptides involved in pain perception and inflammation.19,20 Consequently, local administration of botulinum toxins has emerged as a novel therapeutic option for humans with certain chronic and painful osteoarticular diseases and neuropathies.10,21–24

Botulinum toxin type B can cleave the synaptic vesicle–associated membrane protein I-II.19 This protein is part of the SNARE complex that is responsible for fusion of the vesicle and presynaptic membrane within the axon ending. Therefore, BTXB inhibits presynaptic exocytosis of acetylcholine in the neuromuscular synapse and causes temporary denervation of striated muscle. Botulinum toxin type B can also inhibit the release of other SNARE-dependent neuropeptides (SP, CGRP, and glutamate) involved in the generation and transmission of joint pain to the spinal cord.19 These findings have led to speculation that BTXB might alleviate navicular pain by binding to synovial nociceptor fibers of the PA and inhibiting vesicle release of SP, CGRP, and other neuropeptides potentially involved in the generation and transmission of foot pain to the spinal cord.

Botulinum toxin type A has been used to treat horses with laminitis,25 stringhalt,26 and carpal synovitis.27 In contrast, BTXB has only been used experimentally in horses to decrease anal sphincter tone.28 However, it is plausible that BTXB might also be effective in alleviating chronic musculoskeletal pain and lameness in horses on the basis of reported analgesic properties after local injections of botulinum toxins in rodents and humans.15,19,29 Assuming these analgesic properties do exist, then modulation of neuropeptide release from the unmyelinated nerve fibers of the PA by BTXB might provide analgesia and improve lameness in horses with degenerative injury to the PA.

Therefore, the objective of the study reported here was to investigate the safety and short-term efficacy of intrabursal administration of BTXB to alleviate lameness in horses with degenerative injury of the PA. We hypothesized that a single injection of BTXB into the NB would alleviate chronic lameness in horses with degenerative injury to the PA.

Materials and Methods

Animals—The study was conducted in 2 phases. The first phase was a safety evaluation that involved 3 horses. The second phase of the study involved clinical evaluation of the effects after treatment in 7 client-owned horses.

Safety evaluation and dose determination—Three Quarter Horses between 8 and 12 years of age with radiographic evidence of bilateral degenerative injury of the PA were used to determine the safety for BTXB injection into the NB and to provide preliminary information on effects of BTXB on lameness. Horses selected for this part of the study were housed in stalls for 24 hours prior to baseline lameness evaluations and BTXB administration into the NB of one of the forelimbs. Horses had ad libitum access to food and water. Horses were client-owned animals with naturally occurring degenerative injury to the PA that had been donated to the university for research purposes. Treatment and care of the animals were approved by the University of Illinois Institutional Animal Care and Use Committee.

The NB of 1 affected forelimb of each horse was injected with BTXB (3.0 to 4.4 U/kg). The dose range was based on the range used to transiently decrease anal sphincter tone in horses of another study.28 After the BTXB injection, health and lameness status of each horse were monitored daily for 10 days by one of the investigators (MPS). None of the horses had local or systemic adverse effects during this safety evaluation, and all 3 horses had marked improvement in lameness for the treated forelimb; furthermore, the horse that received the highest dose of BTXB had the most improvement in lameness by day 10 after treatment.

Horses were euthanized on day 11 after treatment, and macroscopic evaluation of the podotrochlear structures of the feet of both forelimbs was conducted. Macroscopic abnormalities detected in the PA of the foot of each horse were consistent with degenerative injury to the PA and similar to those detected in the PA of the untreated contralateral foot. On the basis of the results of this preliminary safety evaluation, we elected to use the highest dose of BTXB for the purpose of maximizing positive clinical effects on lameness during the subsequent phase of the study.

Evaluation of effectiveness of BTXB on lameness in horses with degenerative injury to the PA—Seven client-owned Quarter Horses with chronic (> 6 months) bilateral degenerative injury to the PA were enrolled. Written owner consent was obtained for the participation of each horse. The study protocol was approved by the University of Illinois Institutional Animal Care and Use Committee.

None of the horses had a history of vaccination with Clostridium botulinum toxoid, had undergone surgical procedures, had recent changes in the shoeing schedule or shoe type, had received systemically administered NSAIDs within 14 days preceding the study, or had received intrasynovial treatments. During the study, each horse was housed in a box stall (3.3 × 3.3 m) and was hand walked for 15 minutes 3 times daily.

Degenerative injury to the PA was diagnosed on the basis of several criteria, including bilateral forelimb lameness that was worse when horses were jogging in a circle, ≥ 90% improvement in lameness after palmar digital anesthesia achieved by the injection of 2 mL of 2% mepivacaine hydrochloridea over the palmar digital nerves immediately axial to the ungular cartilages, improvement in lameness by 5 minutes after administration (achieved with radiographic guidance) of 3 mL of 2% mepivacaine hydrochloride into the NB, and radiographic and MRI abnormalities consistent with degenerative injury to the PA.30–32

Diagnostic imaging and interpretation—Standard radiographic views (lateromedial, 45° and 60° dorsoproximal-palmarodistal oblique, and 45° palmaroproximal-palmarodistal oblique radiographic views) of the feet of both forelimbs of each horse were obtained with digital radiography.b Horses were anesthetized, and MRI of the feet of both forelimbs of each horse were obtained with an open 0.25-T magnet.c A 3-plane image was obtained first to ensure correct positioning of the limbs and for orientation of subsequent sequences. The MRI protocol included short tau inversion recovery, T1-weighted spin echo, T1-weighted 3-D gradient echo, and T2-weighted turbo spin echo sequences in all 3 imaging planes. All radiographic and MRI images were reviewed by a board-certified veterinary radiologist (ALM).

Subjective lameness evaluation—Lameness evaluations were conducted and video recorded by one of the investigators (SGN) 5 days before (baseline) and 7 and 14 days after BTXB administration. Lameness evaluations consisted of trotting each horse on hard ground in a straight line and in circles in both directions. Because horses were bilaterally lame, lameness evaluations were conducted on 2 consecutive days at each of the 3 time points. The first day, the forelimb with the least severe lameness was desensitized with an abaxial sesamoid nerve block, which allowed the best evaluation of the forelimb with the most severe lameness. The next day, the forelimb with the most severe lameness was desensitized with an abaxial sesamoid nerve block to enable the best evaluation of the forelimb with the least severe lameness. This study design was used to provide the best assessment of the lameness of each forelimb because the severity of head and neck movement is greatly lessened in horses with bilateral forelimb lameness.33

Treatment—Five days after the initial baseline lameness evaluation, an NB of each horse was injected with 3.8 to 4.5 U of BTXBd/kg (provided in a solution containing 5,000 U/mL); injections were administered with sterile technique and radiographic guidance. The dose used was determined in the aforementioned safety evaluation. The NB of the forelimb with the most severe lameness was injected; thus, treatments were not randomly allocated to ensure a higher baseline lameness score for the limbs that received treatment. Therefore, each horse served as its own control animal, and the contralateral (least lameness) forelimb was not treated.

All horses were maintained on their shoeing schedule (5 to 6 weeks between shoeings) and received the same shoe type (rolled-toe shoes); however, none of the hooves of the forelimbs were trimmed during the study period, except as necessary to be reshod immediately after diagnostic imaging. Physical examinations were performed on each horse once or twice daily; horses were closely monitored for evidence of complications or adverse events, including lameness, weakness, dysphagia, poor muscle tone of the treated forelimb, incoordination, colic, decreased intestinal motility, decreased salivation, urine retention, or recumbency. Sensation of the superficial aspect of the heel of the foot of each forelimb was monitored daily by applying pressure to the skin of the heel with the tip of a ballpoint pen.

Qualitative assessment—Video recordings of all lameness examinations were placed in a random sequence on a DVD to ensure that investigators scoring the lameness were not aware of the treated forelimb of each horse and the time frame (baseline and 7 and 14 days after treatment) for all video recordings. The duration for each video recording was approximately 180 seconds. Three board-certified equine surgeons (NAW, JAB, and MNA) separately evaluated the videos for each of the horses at each time frame and scored the lameness of each forelimb for each of 3 portions of the lameness examination (trotting in a straight line, trotting in a clockwise direction, and trotting in a counterclockwise direction). Lameness scores were assigned by use of a modified version of the American Association of Equine Practitioners’ lameness scale34 (Appendix). Investigators were allowed to view the video recordings as many times as they deemed necessary before entering the lameness score for each of the 3 portions of the lameness examinations into a computer spreadsheet program.e

Statistical analysis—Lameness data were summarized as median and range values calculated on the basis of the lameness scores assigned to each horse by the 3 investigators at each time point. Analysis by use of a mixed linear model with each horse as a subject was used to test for significant differences among lameness scores of the treated forelimbs and among lameness scores of the contralateral forelimbs during the study. A Dunnett post hoc test was used to determine whether the lameness score at each time point was significantly different from the baseline lameness score. In addition, interevaluator agreement was examined by use of a weighted κ. A value of κ = 1 indicated perfect agreement, and a value of κ = 0 indicated agreement equivalent to chance. Agreement was considered poor for κ ≤ 0.20, fair for κ ≥ 0.21 but ≤ 0.40, moderate for κ ≥ 0.41 but ≤ 0.60, good for κ ≥ 0.61 but ≤ 0.80, and excellent for κ ≥ 0.81.35 Commercial statistical softwaref was used to analyze data. Values were considered significant at P ≤ 0.05.

Results

Median age of the 7 horses was 11 years (range, 5 to 14 years), median lameness duration was 12 months (range, 10 to 24 months), and median body weight was 553 kg (range, 490 to 590 kg). All horses had radiographic abnormalities in the navicular bone, including enlarged synovial invaginations (n = 6 horses), loss of a definitive corticomedullary border and increased opacity of the medullary cavity (6), radiolucency in the flexor aspect of the navicular bone (5), and elongation of the distal or proximal (or both) flexor aspects of the navicular bone with concurrent enthesophyte formation at the CSL attachment (5). Magnetic resonance imaging confirmed the presence of abnormalities within the PA, including abnormal short tau inversion recovery and T1-weighted signal in the medullary cavity of the navicular bone compatible with the presence of abnormal fluid (n = 7 horses), full-thickness erosions of the flexor cortex of the navicular bone (7), and fibrillation of the dorsal margin of the deep digital flexor tendon without parasagittal tears (7; Figure 1). Other abnormalities of the PA were CSL thickening (n = 6 horses), synovial proliferation within the NB and adhesions between the proximal recess of the NB and deep digital flexor tendon (5), and mild desmopathy of one of the collateral ligaments of the distal interphalangeal joint (4).

Figure 1—
Figure 1—

Sagittal T1-weighted spin echo image of the foot of a representative horse with degenerative injury to the PA after injection of the NB with BTXB. Notice the large erosion of the flexor cortex of the navicular bone. The navicular bone has a defect in the flexor cortex with a high signal intensity (large white arrow), and there is an area of low to intermediate signal intensity within the medullary cavity (small white arrow). There is also loss of definition of the dorsal aspect of the deep digital flexor tendon and thickening of the CSL (black arrow).

Citation: American Journal of Veterinary Research 75, 3; 10.2460/ajvr.75.3.282

After BTXB administration, horses remained comfortable while walking and had no abnormalities in superficial and deep sensation of the heel region of the treated foot. Two horses developed transient increases in lameness attributable to inflammation in the treated foot 2 days after BTXB administration, but both resolved without further complications within 3 days. However, 1 of these 2 horses was removed from the study on day 8 after BTXB treatment. At the owner's request, that horse was removed from the study and treated with NSAIDs, despite the fact the horse had a modest improvement in lameness evident on day 7 after BXTB treatment.

Differences between qualitative lameness scores assigned by the 3 investigators before and after BTXB administration were evaluated. Agreement of lameness scores among investigators was moderate (mean weighted κ coefficient, 0.42).

Median baseline lameness score for the forelimb with the most severe lameness (ie, the contralateral forelimb with the least severe lameness desensitized with an abaxial sesamoid nerve block) for the 7 horses was 2.5 (range, 1.0 to 4.0) when horses trotted in a straight line, 3.0 (range, 3.0 to 4.0) when horses trotted in a circle and the forelimb with the most severe lameness was on the inside of the circle, and 3.0 (range, 0 to 3.5) when horses trotted in a circle and the forelimb with the most severe lameness was on the outside of the circle. Median baseline lameness score for the contralateral forelimb (ie, the forelimb with the most severe lameness desensitized with an abaxial sesamoid nerve block) for the 7 horses was 0.5 (range, 0 to 3.5) when horses trotted in a straight line, 1.0 (range, 0 to 4.0) when they trotted in a circle and the forelimb with the most severe lameness was on the inside of the circle, and 1.0 (range, 0 to 4.0) when they trotted in a circle and the forelimb with the most severe lameness was on the outside of the circle.

Baseline lameness scores after intrasynovial anesthesia of the NB for the forelimb with the most severe lameness for the 7 horses were significantly (P = 0.01) lower when horses trotted in a straight line (median, 1; range, 0 to 2), in a circle and the forelimb with the most severe lameness was on the inside of the circle (median, 1.5; range, 0 to 3), and in a circle and the forelimb with the most severe lameness was on the outside of the circle (median, 0; range, 0 to 3). However, 6 of 7 horses had residual lameness after the block.

Seven days after BTXB administration, the lameness scores for the treated forelimbs were not significantly (P = 0.15) different than the baseline scores for the 7 horses when they trotted in a straight line (median, 2.0; range, 0.5 to 3; Figure 2). Lameness scores for the treated forelimbs at 7 days after BXTB treatment did not differ significantly for the 7 horses when they trotted in a circle with the treated limb on the inside of the circle (median, 3.0; range, 1.0 to 3.5) and in a circle with the treated limb on the outside of the circle (median, 3.0; range, 0 to 3.5). Fourteen days after BTXB administration, lameness scores for the treated limbs were significantly lower for the 6 remaining horses when they trotted in a straight line (median, 1.5; range, 0 to 3.0), in a circle with the treated limb on the inside of the circle (median, 2; range, 0 to 3.0), and in a circle with the treated limb on the outside of the circle (median, 2; range, 0 to 3.0). In contrast, the lameness scores of the contralateral limbs did not change significantly (P = 0.71) for the 7 horses at 7 days after BTXB treatment (trotting in a straight line [median, 1.0; range, 0 to 3.5], trotting in a circle with the treated limb on the inside of the circle [median, 1.0; range, 0 to 3.0], and trotting in a circle with the treated limb on the outside of the circle [median, 1.0; range, 0 to 3.0]) and for the 6 horses at 14 days after BXTB treatment (trotting in a straight line [median, 0.5; range, 0.5 to 3.5], trotting in a circle with the treated limb on the inside of the circle [median, 0.5; range, 0 to 4.0], and trotting in a circle with the treated limb on the outside of the circle [median, 1.0; range, 0 to 4.0]; Figure 3).

Figure 2—
Figure 2—

Box-and-whisker plots of lameness scores for the treated forelimb in horses with degenerative injury to the PA of both forelimbs that had the limb with the most severe lameness treated by injection of BTXB into the podotrochlear bursa (NB). Lameness scores were assigned for horses when they trotted in a straight line (A), in a circle with the treated limb to the inside of the circle (B), and in a circle with the treated limb to the outside of the circle (C) at each of 3 time points (baseline [5 days before BXTB administration] and 7 and 14 days after BTXB administration). Lameness scores were determined separately by 3 investigators from video recordings; lameness was scored from 0 to 5 by use of a scale modified from the American Association of Equine Practitioners’ lameness grading scale. Results represent data for 7 horses at baseline and day 7 and 6 horses at day 14 because 1 horse was removed from the study on day 8 at the owner's request. Each box represents the interquartile range (25th to 75th percentiles), the horizontal line in each box represents the median, the whiskers represent 1.5 times the interquartile range, and circles represent values > 1.5 times the interquartile range. a,bWithin each panel, time points with different letters differ significantly (P ≤ 0.05).

Citation: American Journal of Veterinary Research 75, 3; 10.2460/ajvr.75.3.282

Figure 3—
Figure 3—

Box-and-whisker plots of lameness scores for the contralateral untreated forelimb in horses with degenerative injury to the PA of both forelimbs that had the limb with the most severe lameness treated by injection of BTXB into the NB. Within each panel, lameness grades did not differ significantly (P = 0.71) among time points. See Figure 2 for remainder of key.

Citation: American Journal of Veterinary Research 75, 3; 10.2460/ajvr.75.3.282

Discussion

Results of the study reported here supported the hypothesis that a single injection of BTXB into the NB of horses with degenerative injury to the PA could temporarily alleviate lameness for at least 14 days without causing systemic adverse effects. Although all horses had modest attenuation of lameness after BTXB treatment, none of them were totally free of lameness. The incomplete alleviation of lameness observed among these horses may have been attributable to the variable degree of lameness and stages of pathological changes in the PA of the treated feet. Horses with a lameness score ≤ 2 had a better clinical response to BTXB administration than did horses with a lameness score > 2. However, the incomplete alleviation of lameness observed among the horses may have been attributable to residual pain emanating from structures of the PA that were not adjacent to the NB and not targeted by the injected BTXB. This possibility was supported by the results after intrasynovial anesthesia of the NB, which was used to confirm pain emanated from the navicular region and to determine the clinical importance of the degenerative injury to the PA.36 All 7 horses included in the study had a positive response to anesthesia of the NB; however, only 1 horse had no lameness after this nerve block. Residual lameness attributable to concurrent lesions of the collateral ligament of the distal interphalangeal joint in 4 horses included in the study was not thought to be a major contributor to the lameness score because all 4 had a marked improvement in lameness in response to anesthesia of the NB.

Incomplete alleviation of lameness after BTXB injection could also have been attributable to interindividual variation in the response or because there was an insufficient amount of toxin in the injected area. It is possible that multiple injections or higher doses of BTXB may be necessary to optimize analgesic effects in horses with degenerative injury to the PA. Another reason for the incomplete alleviation of the lameness after treatment may have been the distribution of antinociceptive fibers throughout the PA in horses. These sensory fibers are distributed over the surface of the palmar aspect of the CSL, distal sesamoidean impar ligament, synovial lining of the NB, and dorsal border of the deep digital flexor tendon.6,9 However, there are several nerve fibers that reach the navicular bone via the synovial lining of the dorsal surface of the CSL and dorsal aspect of the distal sesamoidean impar ligament,6,9 and these fibers may not have been desensitized by intrabursal administration of BTXB.

One of the risks associated with the use of botulinum toxins is systemic signs of botulism owing to the spread of toxin beyond its original injection site.28 This phenomenon is influenced by the dose, concentration, and volume of the injection as well as other factors when injected IM.37,38 We used BTXB for the present study because of another report28 on its use in horses that provided information about the dose used. In that study,28 4 mL of BTXB solution (dose of 0.88 to 2.20 U/kg) did not cause adverse clinical effects; however, transient clinical signs of botulism were observed at a dose of 4.4 U/kg. Given this apparent narrow therapeutic margin, we conducted a safety evaluation with the previously reported dose but a smaller injection volume (0.5 mL). During that evaluation, 3 horses with degenerative injury to the PA received 3.3 to 4.5 U of BTXB/kg in the NB without apparent systemic toxic effects but with marked clinical improvement of lameness. Because the highest dose yielded the best likelihood for improvement in lameness during the safety evaluation, that dose was subsequently used in the present study.

Including the 3 horses used in the initial safety evaluation, there were 2 of 10 horses that had mild transient increases in lameness within 72 hours after BTXB treatment. We speculate that the increase in lameness in both horses may have been attributable to synovitis and a hypersensitivity response to the protein component of the botulinum toxin because transient immune-mediated synovitis after botulinum toxin administration has been reported in humans and other species.18,39 However, we could not confirm our clinical suspicion because we did not perform synoviocentesis and synovial fluid analysis for the affected horses to avoid potential exacerbation of the lameness from sampling of the NB. Nonetheless, the clinical signs resolved without further complications in both horses. Administration of systemic anti-inflammatory medications before BTXB injections may be effective for alleviating transient clinical signs associated with BTXB injections. It is worth mentioning that transient synovitis has also been reported after intrasynovial administration of corticosteroids or hyaluronate in horses and is not an unexpected complication.40

The etiopathogenesis of degenerative injury to the PA is not fully understood; however, predisposing factors include breed, age, faulty conformation, hoof imbalance, and biomechanical forces.1 The end result is progressive degeneration of the navicular bone and associated soft tissues, which result in chronic lameness. Conservative treatment consists of rest or controlled exercise, corrective shoeing, and anti-inflammatory medication.1 Corrective shoeing and NSAID treatment do not always alleviate lameness in horses with degenerative injury to the PA,41 and long-term use of anti-inflammatory medications can be detrimental. Local intrasynovial administration of corticosteroids with or without hyaluronate can alleviate lameness; however, this treatment is not always effective, particularly in horses with severe degenerative injuries to the PA.32,42,43 Tiludronate administration is more effective in horses with recent onset of lameness than in those with chronic lameness.44 Surgery is usually reserved for horses with degenerative injury to the PA that did not respond to conservative treatments or that have become unresponsive to conservative treatments. Navicular bursoscopy and careful debridement of torn fibers of the deep digital flexor tendon and intrabursal adhesions can be an effective treatment option for horses with abnormalities that are localized to the NB.45,46 Alternatively, palmar digital neurectomy is an accepted palliative treatment for horses with unresponsive clinical signs.47,48 Analysis of results of the present study suggested that intrabursal injection of BTXB may be a useful short-term palliative treatment option for alleviating lameness in horses with degenerative injury to the PA. However, the positive effects of BTXB for attenuating lameness in horses with degenerative injury of the PA can be of concern because of the potential abuse of BTXB to mask lameness in horses that participate in competitions.

One of the difficulties encountered during this type of study is assessing the change or response to treatment because of the need for consistent scoring of outcome at various time points. Subjective lameness evaluation by experienced clinicians is the standard for lameness diagnosis and has been extensively used in veterinary research. However, subjective evaluation of mild lameness is not reliable and has poor interobserver agreement.49,50 Results of the present study confirmed these previous observations because the agreement between evaluators was marginally acceptable. Kinetic and kinematic gait analyses have been developed to complement subjective evaluation and provide accurate identification and quantification of lameness in equine research.51 Both kinetic and kinematic gait analyses have been extensively used to evaluate the effectiveness of novel medications, devices, and shoeing techniques in lame horses, but both methods require special equipment and facilities and were not available during the present study. Nevertheless, on the basis of the modest subjective improvement detected in the horses of the study reported here, additional investigation of the effect of BTXB in lame horses by use of objective gait analysis is warranted.

Because degenerative injury to the PA is often bilateral, it would be necessary to treat all of the lame limbs at the time of diagnosis; however, doubling the dose administered would increase the risk of systemic toxicoses or adverse effects.28 It may be possible to reduce the risk of systemic toxic effects by injecting the second limb at a later time, although the required interval needed between injections to avoid unwanted adverse effects is not known. Another potential issue with the use of botulinum toxins is antibody-induced treatment failure in patients that receive frequent injections of the toxins.52

Analysis of results of the present study revealed that intrabursal administration of BTXB was effective for improving lameness in horses with degenerative injury to the PA. A randomized controlled clinical trial is necessary to establish the efficacy and long-term safety of BTXB administration in horses with degenerative injury to the PA before clinical application of this treatment can be advocated. Moreover, other medications that can target neuropeptides within the PA may also have a role in the treatment of degenerative injury of the PA in horses.

ABBREVIATIONS

BTXB

Botulinum toxin type B

CGRP

Calcitonin gene–related peptide

CSL

Collateral sesamoidean ligament

NB

Navicular bursa

PA

Podotrochlear apparatus

SNARE

Soluble N-ethylmaleimide sensitive factor attachment protein receptor

SP

Substance P

a.

Pharmacia & Upjohn Co, New York, NY.

b.

Sound-Eklin, VCA Antech Co, Carlsbad, Calif.

c.

Vet MR Grande, Esoate, Genova, Italy.

d.

Solstice Neurosciences LLC, South San Francisco, Calif.

e.

Excel 2007, Microsoft Corp, Redmond, Wash.

f.

SAS, version 9.2, SAS Institute Inc, Cary, NC.

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Appendix

Modified lameness grading scale used to evaluate lameness during trotting on a hard surface for horses with bilateral degenerative injury of the PA in the forelimbs.

GradeDescription
0No lameness
0.5Uneven gait but cannot identify a consistent head nod
1.0Mild lameness is difficult to detect
1.5Mild lameness is difficult to detect but with an intermittent subtle head nod
2.0Mild lameness with consistent subtle head nod
2.5Mild lameness with consistent subtle head nod and intermittent moderate head nod
3.0Moderate lameness consistently detected
3.5Moderate lameness with intermittent marked head nod
4.0Severe lameness with marked head nod, or a shortened stride
4.5Obvious lameness, marked head nod, shortened stride, and brief periods of the heel touching the ground at every step
5.0Minimal weight bearing

The scale represents a modification of the American Association of Equine Practitioners’ lameness grading scale.35

Contributor Notes

Supported in part by Solstice Neurosciences LLC.

The authors thank Steve Sermersheim, Dr. Sushmitha Durgam, and Dr. Isabella Horn for technical assistance.

Address correspondence to Dr. Gutierrez-Nibeyro (sgn@illinois.edu).