Reduction of self-mutilating behavior and improved oromotor function in a patient with Lesch-Nyhan syndrome following botulinum toxin injection: A case report

1. Introduction

Lesch-Nyhan syndrome (LNS) is a rare, X-linked metabolic disorder resulting in hyperuricemia, intellectual disability, movement disorder, and self-mutilation [1]. LNS is caused by mutation in the HPRT1 gene leading to deficient activity of the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT) normally involved in the purine salvage pathway [1]. Multiple phenotypes have been described over time, with the classic neurobehavioral phenotype associated with less than 1% HPRT activity [1]. The gold standard for diagnosing LNS is measuring HPRT activity [1]. Pearson et al. have described LNS as one of the “genetic mimics of cerebral palsy” with dystonia often developing between ages 6 and 24 months [2].

Self-mutilation continues to be a significant barrier in caring for patients with LNS. This behavior typically develops between ages 1 and 6 years and will often involve biting of the fingers, hands and lips [3]. In some patients the self-injurious behavior precedes the diagnosis of LNS [3]. Children with LNS may be aware of and distressed by the compulsion to harm themselves, at times demonstrating remorse after acts of aggression [4]. Treatments to help reduce these challenging behaviors have been widely investigated. Restraints, behavioral treatment, dopaminergic medications and deep brain stimulation (DBS) have been variably successful in reducing the self-harm seen in LNS [4].

The aim of this case report was to assess symptomatic relief after routine injections of onabotulinum toxin (BoNT) to the masseter muscles in a patient with both LNS and spastic dystonic quadriparesis who demonstrated self-injurious behavior and had speech and feeding difficulty related to oromotor dystonia.

2. Case report

A 13-year-old boy with LNS and spastic dystonic quadriparesis presented with self-injurious behaviors despite multiple treatment approaches. His self-mutilation began with hand-biting at 4 years of age. He was able to understand and follow instructions to stop biting his hands, but he would quickly resume this behavior in a compulsory manner. He was followed by psychiatry and was placed in gloves as well as bilateral elbow extension splints to block hand-to-mouth movement. At 8 years of age the patient underwent genetic testing when uric acid crystals were found in his diaper, and he was ultimately diagnosed with LNS. His self-injurious behaviors and associated anxiety, as well as dystonia and spasticity, progressed despite multiple medication trials over time including carbidopa-levodopa, fluoxetine, gabapentin, clonazepam, olanzapine, and oral baclofen. Clonazepam was noted to help reduce the anxiety associated with his self-injurious behaviors but did not decrease the behaviors. Physical protective layers including a mouthguard/pacifier, along with oral motor kineseo taping were also attempted; both were noted to help but the benefits remained overall inadequate. At 11 years of age he had several teeth removed to help prevent lip biting, but his self-injurious behavior continued. He ultimately received an intrathecal baclofen (ITB) pump at 11 years of age. There was some improvement of self-mutilating behavior during his inpatient rehabilitation hospitalization following placement of the ITB pump. However, his self-biting behaviors later returned and progressed despite increased baclofen dose, additional wheelchair modifications, and continued use of elbow extension splints.

The decision was made to trial BoNT injections to the patient’s masseters at 11 years of age; this is an off-label use of BoNT. The decision to inject the masseters was based on previous reports, most notably the case report by Dabrowski et al. in 2005 [5]. Forty units of BoNT were injected into bilateral masseter muscles (20 units to each side) utilizing ultrasound and electric stimulation guidance. The patient tolerated the injections well with no adverse or unexpected events. At follow-up evaluation 6 weeks post-injection, the patient was noted to have reduced self-mutilating behaviors, especially biting. At 16 weeks post-injection, the patient was re-evaluated again and noted to only require a unilateral elbow extension splint, where he previously had required bilateral splints. At 5 months post-injection by which time the BoNT effects may have worn off, the patient was demonstrating increased biting of his lip again. The decision was made to repeat BoNT injections into bilateral masseter muscles; 50 units were injected into his bilateral masseter muscles (25 units to each side). There were no problems with chewing, swallowing or breathing after the injections. Post-injection symptom relief was again noted, with reduced self-mutilating behavior lasting 4 to 6 months before the behavior resumed. BoNT injections to bilateral masseters were given for a third and fourth time (50 units each time), with the same pattern of 4–6 months symptom relief observed between each injection.

There was direct temporal association with measurable and functional gains in speech therapy and the patient’s BoNT injections into the masseters. He demonstrated significant improvement in speech, including breath support, volume, articulation, number of utterances attempted, and number of words per utterance (achieved an average use of 3–4 words with some 7 word utterances, as opposed to a previously reported average range of 1–2 words). Regression in speech was noted to directly coincide with time elapsed between BoNT injections. The patient received his next BoNT injection to bilateral masseters and again made significant gains in speech therapy, particularly with speech articulation and length of utterances. He was evaluated in speech therapy using the Photo Articulation Test Third Edition (PAT-3) as a screening tool. As it was used as a screening tool, the PAT-3 was not scored according to instructions or used as a standardized measure of articulation. Directions for screening implementation included imitation of the evaluator’s verbal model. Errors in consonant production and in consonant blend production (e.g. bl, sp) at the single word level were analyzed. As the PAT-3 was used for screening purposes in this assessment, there were 75 possible accurate productions. Prior to starting BoNT injections he initially yielded 46 errors out of a possible 75 errors. After 4 BoNT injections over the span of 2 years, he completed imitation tasks yielding an improvement to 21 errors out of a possible 75 errors. Speech improvements were noted mostly in the area of fricative sound production and in decreased omission of final consonants in words.

Feeding improvements were also noted. After the third BoNT injection, he had a temporary increase in drooling in the first days following the injections, possibly reflective of worsening secretion management due to reduced tone in the masseter muscles. Three weeks following the injections, however, he showed improvements in his secretion management as well as his ability to chew and swallow with no gagging or coughing. As the BoNT wore off months later, eating became challenging again.

3. Discussion

This patient had self-mutilating behaviors in the setting of LNS and spastic dystonic quadriparesis. ITB therapy provided some benefit, but the effects were short-lived even with dose increases. BoNT injections were pursued after alternative treatments including trials of multiple oral medications as well as physical restraints were not achieving the desired reduction in self-mutilation. Reduction in self-biting was demonstrated as evidenced by both parent and therapist reports and the decreased use of restraints.

A number of studies have investigated the effect of BoNT injections to the masseter muscles in patients with dystonia leading to self-biting. In 2006, Schneider et al. described two patients with pantothenate kinase-associated neuro degeneration (PKAN) resulting in oral-buccal dystonia with jaw-closing spasms. Both patients demonstrated considerable symptomatic relief following BoNT injections into the masseter muscles [6]. In 2016, Brissaud et al. described successful BoNT injections into the masseters and orbicularis oris in a 17-month-old female with tongue-biting from oromandibular dystonic movements [7]. BoNT injections have also been effective in cases of bruxism [8, 9].

There have been limited investigations of BoNT in patients with LNS-related self-mutilation. Gutierrez et al. presented a case in which BoNT was injected into the perioral muscles of a patient with LNS who continued to harm himself despite having several teeth removed and for whom DBS was not readily available; the masseters were not injected due to concern for possible spread to pharyngeal muscles and subsequent dysphagia [10]. To our knowledge there has been one report describing the effect of BoNT injections to the masseters in a patient with LNS; in 2005, Dabrowski et al. reported reduced self-mutilating behavior in a 10-year-old boy with LNS after multiple injections of BoNT into bilateral masseters [5]. Our findings are well aligned with those in the case presented by Dabrowski.

In addition to reduced self-injurious behavior, our patient demonstrated significant improvements in oromotor function. There have been reported cases of improved speech and mastication following BoNT injections into the masseters in cases involving stroke-induced trismus and chorea acanthocytosis-related oromandibular dystonia [11, 12]. Speech articulation has also been noted to improve following BoNT injections to the masseter muscles in LNS [5]. Our patient had objective improvement in speech therapy with increased speech volume and reduction in total articulation errors on the PAT-3 administered with modifications. To our knowledge, this is the first report of enhanced feeding and objective, measurable gains in speech following BoNT injections into the masseters in a child with LNS. Within the limitations of observation of a single patient, it seems relevant that this patient’s improvements in speech and mastication waxed and waned along the same timeline of his BoNT injections.

As with any BoNT injections, consideration of potential adverse effects is important especially when injecting head/neck musculature and glands. Risks of BoNT injections have been known to include difficulty breathing, dysphagia and weakness; therefore, the risks and benefits of injection to the masseters should be carefully weighed for each patient. Further investigation of the role of BoNT in reducing LNS-related self-mutilating behaviors is indicated to establish optimal dosing. Additionally, investigation of the timeline of BoNT intervention may be useful to determine if earlier intervention could more effectively inhibit self-injurious behaviors.

4. Conclusions

This case presentation highlights and reasserts the benefits of BoNT injections in reducing self-mutilating behaviors as well as improving oromotor function in a patient with LNS. The current conventional treatments for these behaviors often involve restraints, invasive surgery (e.g. DBS, ITB, teeth removal), and systemically acting, psychoactive medications with possible side effects. BoNT injection is a more targeted therapy that may benefit this population by improving quality of life through enhanced function, communication, and patient safety. As a result, BoNT injections should be considered among first line therapies for LNS, and exploration in clinically similar disorders is warranted.