Out of the spasticity box: Off-label uses of botulinum toxin in children

Abstract

Botulinum toxin is frequently used as a therapeutic for a variety of non-FDA approved indications in children. This narrative literature review explores three off-label uses of botulinum toxin in pediatric conditions including congenital muscular torticollis, spastic trismus, and neonatal brachial plexus palsy. While more research is needed to establish treatment, dosing and localization guidelines for the use of botulinum toxin in these commonly treated conditions, available evidence is discussed.

In addition to FDA approved indications, botulinum toxin (BoNT) has been used empirically in a variety of neurologic, orthopedic, otolaryngologic, urologic, gastrointestinal, and pain disorders. We describe three off-label uses of BoNT in children.

Congenital muscular torticollis (CMT) is an abnormal positioning of the neck that is recognized shortly after birth and involves shortening of the sternocleidomastoid (SCM) muscle. The upper trapezius and scalene muscles can also be involved. Infants with torticollis typically tilt their head toward the ipsilateral shortened muscle and rotate toward the contralateral side. The prevalence of CMT varies from 0.3% to 2.0% in one study [1] to as high as 16% in another [2], which would make CMT the most common congenital musculoskeletal abnormality. Although many theories have been proposed, the cause of CMT remains unknown. Early treatment of CMT includes physical therapy, repositioning and use of a tubular orthosis. Surgery is reserved for recalcitrant cases. BoNT can be used in children with persistent torticollis who fail conservative management. It is theorized that the temporary weakening of contracted neck muscles with BoNT allows for greater ease of stretching the affected neck muscles and improved ability to strengthen the contralateral muscles [3]. Another study suggests that BoNT could potentially inhibit SCM fibrosis through regulating fibroblast and inhibiting myofibroblast differentiation [4]. A few retrospective studies have shown BoNT-A to be effective in improving cervical range of motion and head tilt in children ages 3–27 months (mean age range 7.6 to 14 months) [3, 5, 6]. Dosing ranged from 20–50 units or 2–3 units/kg in the SCM and 25–35 units in the upper trapezius muscle, with a combined SCM and upper trapezius dose of 25–80 units in one study [3, 5, 6]. Adverse events were rare and transient and included dysphagia, neck weakness, pain and bruising in 7–13.3% [3, 5].

Spastic trismus (ST) is a clenching of the jaw, caused by hypertonia of the muscles of mastication [7]. While the incidence of ST in children with acquired or congenital brain injury is not known, it is widely recognized as the cause of multiple clinically important implications such as difficulties with mastication, oral phase swallowing, articulation, oral hygiene and potential airway complications [8, 9]. ST can also lead to bruxism, which itself is associated with dental complications and pain [7, 10]. Currently, there are no standardized treatment algorithms for the treatment of ST in brain injury. Both manual mobilization therapies and enteral antispasmodics may be limited in efficacy or have undesirable side effects. Despite a relative paucity of evidence, BoNT injections to the muscles of mastication have been demonstrated to be effective in the improvement of ST [8, 9, 10, 11, 12, 13]. Masseter and temporalis muscles are the most commonly reported targeted muscles, with some case reports also targeting the medial and lateral pterygoid muscles [13]. Both BoNT-A and B have been reported as effective. There are two pediatric case reports describing use of BoNT in a 3-year-old and a 9-year-old [11, 13]. Dosing ranged from 50 total units of BoNT-A, divided in the bilateral masseters, to 300 units total divided into bilateral masseters, temporalis, medial and lateral pterygoids. Of note, while this large dose was noted to be effective, there were systemic side effects reported [13].

Neonatal brachial plexus palsy (NBBP) leads to muscle imbalance in the upper extremities resulting in functional limitations. Most NBPPs affect the upper plexus leading to restriction of shoulder external rotation, abduction and flexion as well as elbow flexion weakness and wrist flexion posturing, commonly described as Erb’s palsy. Shoulder internal rotation posturing can be caused by imbalance and eventual shortening of the pectoralis major, latissimus dorsi, teres major and subscapularis muscles. Careful clinical evaluation is necessary to determine if the limited range of motion and action of upper extremity movements is due to differential weakness or due to co-contraction of muscle groups [14]. BoNT-A can be used to treat shoulder internal rotation/adduction contractures, elbow flexion/extension contractures and forearm pronation contractures [14]. Ultrasound has been used with increased frequency for injection localization in NBBP [15]. Therapy and possibly orthotic bracing can augment the improvement in shoulder external rotation following injections [16]. Elbow flexor weakness leading to elbow extension contracture is common, and BoNT injections into the antagonist triceps muscle can improve elbow flexion [16]. Forearm pronation contractures due to weakness of the supinator muscle can be treated with BoNT to the pronator teres and/or pronator quadratus, though studies are more limited compared to shoulder internal rotator injections [14, 15, 16]. Toxin dosing varies by muscle but is often reported as 0.5–1 unit/kg in smaller muscles such as in the forearm, and 1–2 units/kg in larger muscles of the shoulder [15, 17, 18], with a maximum of 10 units/kg in one study [16].

In summary, although FDA indications are limited to spasticity in children, BoNT is utilized in many pediatric conditions that are unique in nature and considered off-label indications. More research is needed to establish treatment, dosing and localization guidelines for the use of BoNT in these commonly treated conditions. While possible, it is doubtful that these disorders will receive the same funding for the randomized controlled studies necessary to obtain FDA approval, which was recently accomplished for children with spasticity. Creative and collaborative networks that track indications, dosages, localization, and adverse events could potentially provide lower levels of evidence for the use of BoNT in the absence of adequate funding.