Chemoprotection with botulinum toxin following proximal hamstring-Ischial tuberosity avulsion fracture repair

Abstract

Introduction

Surgical treatment for avulsion injuries of the proximal hamstrings has gained increasing popularity over the past decade. Despite good outcomes, early failures have been noted and have been attributed to slipping and falling, postoperative muscle spasm, or early mobilization. In a recent review of hamstring repair rehabilitation protocols, it was shown that there is marked variability in post-operative management. Post-operative bracing with limiting knee extension and hip flexion is the standard of care in most early rehabilitation protocols. Braces with limitation of hip flexion and knee locked in 90⁰ flexion can be awkward, cumbersome and create fall risk.

Chemoprotection has more recently been proposed to be an alternative approach to prevent tendon repair failure and controlled mobilization which has been shown to be superior to complete immobilization. We present the first case series of the use of botulinum toxin for chemo-protection of the proximal hamstring ischial avulsion repair, demonstrating its safety and efficacy.

Methods

Retrospective case series at a tertiary children’s hospital which included patients <18 years of age who underwent interventional treatment for proximal hamstring avulsion injuries of the ischium utilizing botulinum toxin as a chemoprotective agent. Data collected included demographic data, injury and treatment details, imaging, post-operative rehabilitation and return to activity. Descriptive statistical analysis was conducted.

Results

Five male patients with mean age 14 years (12–17) were included in the study. All were sports related non-contact injuries. Radiographs showed displaced avulsion fractures in all 5 patients. All patients had failed conservative management initially; mean time to surgery from initial injury was 34.4 weeks. 4 patients underwent open reduction and internal fixation (ORIF), 1 patient with less displacement had bone marrow aspirate (BMA) injection; all had chemoprotection using botulinum toxin injected in the hamstrings. No patient required hip immobilization or knee immobilization locked to 90°. We elected to use a brace locked at 20° knee flexion in 2/5 patients. All patients underwent supervised physical therapy and achieved symmetric knee range of motion (ROM). Post-operative radiographs confirmed healing of the avulsion fracture in all 5 patients and they all returned to previous level of activity at mean 32 weeks (21–43) from surgery. None of the patients had a hamstring re-injury at mean follow up of 27 months (11–42).

Conclusion

Our case series is the first in literature that shows the safety and efficacy of chemoprotection with botulinum toxin for the post-operative management of avulsion injuries of proximal hamstrings, by minimizing the need for cumbersome bracing and allowing controlled motion during physical therapy.

1. Introduction

Avulsion injuries of the proximal hamstrings have shown good outcomes after surgical management.^{1, 2, 3, 4} However, postoperative management is incredibly variable.^5,6 Early rehabilitation strategies concentrated on limitation of hip flexion and knee extension to reduce the strain on the repaired, bi-articular hamstring musculotendinous unit.^{3,5, 6, 7} This limitation of range of motion was primarily achieved by bracing of the hip, knee or both joints and was awkward and cumbersome.^{2, 3, 4,8,9} Despite the bracing’s awkward nature, it was deemed necessary to avoiding premature or excessive load that may disrupt repair.¹⁰ The competing challenge of successful tendon repair relies on balancing the mechanical loading that facilitates healing. Dosing the appropriate mechanical load is difficult for the patient and care provider to control and this can be further amplified by muscle spasms post-operatively or during rehabilitation leading to failure in young athletes.^8,11

Chemoprotection has more recently been proposed to be an alternative approach to prevent tendon repair failure.^12,13 It can provide controlled mobilization which has been shown to be superior to complete immobilization.¹⁴ We present the first case series of the use of botulinum toxin for chemo-protection of the proximal hamstring repair demonstrating its safety and efficacy.

Methods: This was a retrospective study at a tertiary children’s hospital after approval from the Institutional Review Board. We included patients <18 years of age who underwent treatment for proximal hamstring avulsion injuries with the use of adjunctive botulinum toxin as chemoprotection during the rehabilitation process. Patients with less than 6 months follow up after surgery were excluded. Data collected included demographic data, injury and treatment details, radiology imaging, post-operative rehabilitation and return to activity. Descriptive statistical analysis was conducted and summarized as means with range values or frequencies.

Results: Five patients, all of them males with mean age 14 years (12–17) treated over a period of 4 years from 2016 to 2019 were included in the study. Average height was 170 cm (159–183), average weight 60 kg (49–68) with mean BMI of 20 (19–22). All 5 patients sustained a hip injury during non-contact sports activities. The most commonly implicated sport was track and field (2/5 patients). The laterality of injury was 4 on the left and 1 on the right lower extremity. Radiographs showed avulsion fracture in all 5 patients (Fig. 1). 3 patients had magnetic resonance imaging for to completely appreciate the injury pattern. All patients failed conservative management initially with rest and rehabilitation. The patients either had persistent pain while sitting for prolonged periods of time, pain with sitting, or were unable to return to sports. Pre-op pain scores was mean 5.6 out of 10 (range 3–7). The mean time to surgery from initial injury was 34.4 weeks (7.5–82.5). 4 patients underwent open reduction and internal fixation (ORIF) using the sub-gluteal approach with a transverse incision in the prone position. The avulsed fragment was fixed with either screw fixation, anchor fixation or a combination of the two which was based on the size of the avulsed fragment and quality of the bone and tissue. These 4 patients had 1.4 cm or greater displacement of the avulsion. The remaining patient with symptomatic but less displaced avulsion had bone marrow aspirate (BMA) injection at the level of the avulsion. This was completed by initially obtaining 12 cc of bone marrow percutaneously from the iliac crest before being injected around the ischial tuberosity under ultrasound guidance. To take the tension off the repair, all five patients had chemoprotection using botulinum toxin injected in the hamstrings, 100 units for the ORIF patients and 200 units for the BMA injection patient. Only the initial two out of five patients used a brace locked at 20° of knee flexion; one patient used it for a week and the second patient for 3 weeks. Subsequent patients did not utilize a brace postoperatively based on the lack of perceived need following the experience of the first two patients. None of the patients had a fall during the post-operative period. All patients underwent supervised physical therapy with the following progression:1. Passive and active assisted range of motion (ROM) initially 2. gentle active ROM 3. isometric activities 4. closed chain strengthening and static proprioceptive activities 5. Concentric to eccentric strengthening 6. Release to dynamic activities such as jumping. Weight bearing as tolerated was initiated at mean 5.8 weeks (4.4–6.8) and all patients we able to achieve symmetric knee range of motion (ROM). Post-operative radiographs showed healing of the avulsion fracture (Fig. 2) in all 5 patients and they all returned to previous level of activity at 32 weeks (21–43) from surgery. Final post-operative pain level was at mean 0.4/10 (range 0–1) and none of the patients had a hamstring reinjury at mean follow up of 27 months (11–42).

Fig. 1.

Pelvis radiograph showing a displaced avulsion fracture of ischial tuberosity.

Fig. 2.

Post-operative radiograph showing healed fracture after fixation with a screw and anchors.

2. Discussion

Current literature recommends surgical management of proximal hamstring if conservative therapy fails and the patient desires to return to higher level of competition/function, or there are complications including nerve involvement.^3,4,9 When operative repair is indicated, open reduction and internal fixation is generally the preferred method.^{1, 2, 3, 4,9}

The surgical repair of these injuries can be complicated by excessive muscle contraction leading to failure and need for repeat surgery.⁸ (Table 1) Marked variability is found in both the composition and timing of rehabilitation components across the various complete proximal hamstring repair rehabilitation protocols.⁵

Table 1.

Literature review- Failures of surgery and causes of failures.

Study	Early Failure Rate	Proposed Failure Mechanism	Postop Rehab Protocol
Beidert et al., 2015	1/3	Post op muscle spasm
Kaeding et al., 2017	2/38 1 at 5 weeks 1 partial rupture at 10 weeks	No immobilization, limited weightbearing
Wood et al., 2008	1/72	Slipped and fell four weeks postop	Some patients used brace, but patient reinjured did not have brace
Gidwani and Bircher, 2007	1/12	“full reduction had been difficult to achieve medially. The fixation failed with breakage of the inferior screws	No splintage used, but patients asked to toe touch weight bear on affected side for 8 weeks
Sarimo et al., 2008	2/41 (see below) 2 required re-operation within 6 months, 3 others required in 11 months or later	One patient lost balance leading to heavy weight bearing and muscle contraction three weeks postop Another attributed to overly aggressive postop rehab contributed to partial re-rupture Other three without attributable cause, later reoperation	TTWB 2–3 weeks Pool exercises at 3–4 weeks Cycling at 4–6 weeks Isometric exercises at 4–6 weeks ROM exercises started 5 weeks postop Running 2–4 months postop
Folsom and Larson, 2007	1/26	Re-rupture at 4 months following slip and fall	Standard knee brace at 60–90° flexion, gradually opened to full extension at 4–6 weeks Aggressive strengthening exercises delayed until 2–3 months postop
Rust et al., 2014	2/72	One sustained re-rupture of acute repair after fall, and one suffered partial re-rupture treated non-operatively	Postop brace applied with either 60/90° knee flexion, which was gradually progressed to full extension over 4–6 weeks when WBAT was allowed.

PWB= Partial weight bearing, NWB= Non weight bearing, TTWB- Toe-touch weight bearing, WBAT = weight bearing as tolerated.

Many forms of protection have been utilized in the past to prevent postoperative tendon repair failure, including mechanical limitation of eccentric contraction (bracing) and prevention of load (non-weight bearing). Over 71% of rehabilitation protocols in literature for hamstring repair surgery recommend bracing, knee or hips; for knee orthoses, bracing in early reports was recommended with the knee locked at 90° of flexion and the hip orthoses limiting flexion to 45°.⁵ This bracing is quite awkward and makes rehabilitation and mobility cumbersome.^{3, 4, 5,9,15,16} Some authors also recommended custom made orthoses.¹⁷ However chemoprotection was not identified as a postoperative adjunctive therapy in the proximal hamstring repair rehabilitation rubric.⁵

Recently, botulinum toxin has been incorporated as an adjunctive modality to protect tendon repair and is termed chemoprotection¹² or bioprotection.¹³ While its historical use has been primarily described in association with cerebral palsy or other upper extremity conditions, the underlying mechanism remains the same: weakening the entire muscle through selective blockade at the neuromuscular junction level of individual muscle fibers.

Dosing of botulinum toxin is based primarily in the cerebral palsy literature and is based upon various dosing strategies: 1. 50–75 units/per muscle group with a maximum dose of 300–400 units per patient in multi-level injections 2. Recommended dose per muscle groups for medial and lateral hamstrings of 1–5 units/kg/body weight. 3. Dose per muscle depends on the muscle volume, the amount of spasticity and the degree of the muscle’s involvement and the dosage can range from 2 to 29 U/kg/body weight.¹⁸

Based on the available literature, in our series, we chose to dose per muscle group, with 50 units in both the medial and lateral hamstrings. BMA patient received a higher dosage as there was no fixation of the fragment.

Bioprotection with botulinum toxin via intramuscular injection was shown to be effective first in an Achilles tendon model in the rat, such that the muscle was incapable of actively producing enough force to rupture the repaired Achilles tendon.¹³ Multiple clinical studies have followed with successful use in zone 2 finger flexor tendon repairs,¹² distal biceps tendon repair,¹⁹ thumb MCP radial collateral ligament reconstruction,²⁰ with the benefits of decreased stress placed on the repair, and decreasing pain associated with the repair.

Based up basic science studies in a rat model,¹³ botulinum toxin provided up to a 75% reduction in twitch and tetanus contractions at one week, 50% or greater for one month and back to normal at 6 months. This represented a 5-10-fold reduction in force required to overcome repair for up to 4 weeks following repair. A similar basic science study in rabbits compared chemoprotection, casting and neither after Achilles repair.²¹ The chemoprotection group appeared biomechanically equivalent to healthy tendons, whereas the casting demonstrated weakness and the no treatment group all failed.

This case series suggests that botulinum toxin’s clinical use may be extended to its use as a rehabilitative adjunct following the operative repair of ischial tuberosity avulsion fractures. Chemo denervation in the setting of bone marrow aspiration, as opposed to ORIF, could be even more important than in ORIF cases because the fracture lacks the mechanical strength conveyed by the fixation placed during ORIF. Our study supports previous literature that PRP or BMA may be an alternative approach to these fractures with minimal displacement that have failed conservative treatment.^22,23

After a thorough review of literature on this surgery and comparing it with our study, the post-operative use of bracing in our patients is evidently less than previous studies (Table 2). Despite the minimal use of post-operative bracing, the overall satisfactory outcome and time for return to play for our case series is similar to previous series in literature^{1,2,4,8,16,24} which is suggestive of the safety and efficacy of chemoprotection.

Table 2.

Post-operative bracing and rehabilitation-comparing our study with literature.

Study	Wt.-bearing post op	Full weight bearing Initiation	Degree of brace initial	Degree of brace later	RTS time	PT notes
Shilt et al.	3 TTWB, 2 PWB	5.86 weeks (4.43–6.86)	3- no brace 2- brace 20°	3- no brace 1- 10–90° 1–30°, increasing extension by 10°/week	32.06 weeks (21–43.28)	Progression from passive ROM→gentle active ROM→ isometric activities→ closed chain strengthening and static proprioceptive activities, eccentric to concentric strengthening→ dynamic activities
Wood et al., 2008 (72 patients w/hamstring avulsions)	PWB for 6 weeks	6 weeks	Up to 90° for maximum of 8 weeks	Extension limitation sequentially reduced as permitted by hamstring tension	79% returned to pre-op level by 6 months	Stretching and closed chain strengthening started at 3 months
Lefevre et al., 2012 (34 proximal hamstring tears)	PWB possible immediately	“walking is begun early (24–48 h)”	Rigid brace at 30–45° flexion for 3–5 days	Articulated brace limiting extension for 45 days	5.7 ± 1.6 months (2.3–9.3months)	Early isometric exercises with knee in 30–45-degree flexion Active rehab beginning at 6 weeks with closed chain exercises Jogging at 12–16 weeks Strengthening with isokinetic then eccentric exercises.
Cohen and Bradley, 2007 (review of surgical management)	TTWB for 10–14 days	25% WB at 4–5 weeks FWB at week 6	Custom hip orthosis limiting hip flexion to 15–30°	Brace discontinued by week 6	8.5 months	2 wks – passive ROM 4 wks – gentle active ROM 6 wks – activities including isotonic exercises with limited ROM and closed chain strengthening 8 wks – dynamic strengthening 10 wks – jogging
Biedert, 2015 (3 ischial tuberosity fractures)	NWB for 6 weeks	PWB at 6 weeks CWB at 10–12 weeks	Harness device holding knee in 90-degree flexion for 4–6 weeks	Wks.’ 1–3: Passive ROM allowed 90-45° wks. 4–6: passive ROM allowed 90-10°	6 months (planned/described)	Passive ROM for first 6 weeks

PWB= Partial weight bearing, NWB= Non weight bearing, TTWB- Toe-touch weight bearing, WBAT = weight bearing as tolerated.

Limitations: The limitations of this study include a small sample size of patients with no control group. However, in this age group, the sample size is consistent with or larger than many others case series reported in the literature. Additionally, it is a retrospective study and did not include a patient directed outcome measures. This study should serve as a pilot study for future prospective, randomized, multi-center study to include larger number of patients, possible use of histologic markers, muscle strength grading and documentation of patients’ satisfaction scores is recommended.

3. Conclusion

Our case series is the first in the literature that demonstrates the safety and efficacy of chemoprotection with botulinum toxin as rehabilitative adjunct for the post-operative management of avulsion injuries of proximal hamstrings, by minimizing the need for cumbersome post-operative bracing and allowing controlled motion during physical therapy.

Institutional review board statement

The study was reviewed and approved by the Baylor College of Medicine Institutional Review Board.

Informed consent statement

No consent as it was a retrospective study.

Statement of equal authors’ contribution

We provide assurance that each author fulfills authorship criteria based on the substantial contributions to the study.

CRediT authorship contribution statement

Jeffrey Shilt: Conceptualization, Investigation, Methodology, Writing - review & editing. Grant McHorse: Methodology, Writing - review & editing. Alexis Moisiuc: Investigation, Methodology, Writing - review & editing. Indranil Kushare: Methodology, Writing - review & editing.

Declaration of competing interest

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. No conflict of interest is to be declared.