Is botulinum toxin effective and safe for motor and phonic tics in patients affected by Tourette syndrome? A Cochrane Review summary with commentary

The aim of this commentary is to discuss from a rehabilitation perspective the published Cochrane Review ‘Botulinum toxin for motor and phonic tics in Tourette's syndrome’ by Pandey et al.,1 under the direct supervision of Cochrane Movement Disorders Group. This Cochrane Corner is produced in agreement with Developmental Medicine & Child Neurology by Cochrane Rehabilitation. According to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, Tourette syndrome is a neurodevelopmental disorder, commonly associated with attention-deficit/hyperactivity disorder and obsessive–compulsive disorder.2, 3 This condition typically begins in childhood or adolescence and is characterized by several motor and some vocal tics, usually accompanied by premonitory urges, occurring daily for over 1 year, and an absence of secondary causes such as substance abuse or neurological disorders (i.e. other movement disorders).2 First described in 1825 and considered very rare until the early 1980s, the prevalence of Tourette syndrome is about 1% in the paediatric population, affecting males up to 4 times more than females.4 Neurophysiological investigations suggest that complex alterations of dopamine and gamma-Aminobutyric acid metabolism and frontal-subcortical neurotransmission occur in Tourette syndrome, particularly involving basal ganglia.5 However, the pathophysiology of this condition is still unclear, leading clinicians to use countless treatment strategies including conservative and surgical options with different mechanisms of action, particularly modulating adrenergic, dopaminergic, or glutamatergic neurotransmission. Motor tics may interfere with normal movement and may cause significant impairment in daily functioning, particularly in social and occupational areas.6, 7 As strongly recommended by the American Academy of Neurology (AAN),8 functional impairment related to tics must be assessed from the patients’ perspective. In this context, rehabilitation, as a highly person-centered health strategy designed to enhance functioning, may represent a core management approach for patients with Tourette syndrome.9 Rehabilitation consists of several interventions addressing functional limitations, including drugs. In Tourette syndrome, pharmacotherapy is usually indicated for patients who experience psychosocial and/or functional impairment.8 In this population, botulinum toxin injections may be considered to treat localized tics, particularly if these affect neck and/or eyes muscles, but also to reduce phonic tics and coprolalia.8, 10 Botulinum toxin, a neurotoxin that inhibits acetylcholine release at the neuromuscular junction, is approved by the Food and Drug Administration (FDA) to manage different conditions, including spasticity and cervical dystonia.11 The evidence drawn from this Cochrane Review can help patients affected by this condition to improve their functioning and quality of life, and might support physiatrists in choosing an adjunctive treatment option for Tourette syndrome, for which, to date, there is no definitive cure. The aims of this Cochrane Review were to assess the effectiveness of botulinum toxin injections in reducing focal motor and phonic tics in patients affected by Tourette syndrome as well as to investigate the safety of this intervention in the same population. The population addressed in this review included people with Tourette syndrome with motor or phonic tics. The intervention studied was botulinum toxin, compared to placebo or other medications. The primary outcome studied was severity of motor tics, measured by videotaped tic count and assessed through both the Yale Global Tic Severity Scale and the Shapiro Tourette Syndrome Severity Scale. Secondary outcomes investigated were premonitory urge and sensation, and adverse events. The authors searched for studies that had been published on the Cochrane Movement Disorder Review Group Specialized Register, the Cochrane Central Register of Controlled Trials, Embase, MEDLINE, BIOSIS previews and conference proceedings (International Congress of Parkinson’s Disease and Movement Disorders), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform, up to 25th October 2017. The review included only one randomized, cross-over 3-year study, conducted in Canada and performed on 18 patients with Tourette syndrome (age range 15–55y), most of whom (n=14) had mild and non-disabling motor impairment and eight received oral drugs. This trial was free from all risk of bias, except for selection bias because of unclear allocation concealment since authors did not define the randomization method. However, the level of evidence of all outcome measures was downgraded because most patients had mild motor tics (poor generalization), and due to the very small sample size with wide confidence intervals. The review shows that single botulinum toxin injection is effective in reducing the severity of motor tics (–37%) and premonitory urge (–94%) at very short-term, although the safety profile was questionable (32 adverse events, mostly non-disabling weakness, were reported in the intervention group vs 5 in the placebo group). The authors concluded that, considering the overall very low quality of evidence, it is uncertain if botulinum toxin injections are effective and safe for treating patients with Tourette syndrome, and it is very likely that further studies might change these findings. This Cochrane Review aimed to investigate benefits and harms of botulinum toxin injection in adolescents and adults affected by Tourette syndrome. However, a single randomized controlled trial, including only 18 patients, was considered according to selection criteria of the systematic review. Moreover, taking into account the overall very low quality of the evidence, the research question remains unanswered. Although Tourette syndrome tends to improve in adulthood, this condition can have serious repercussions on the emotional and affective status because of the social stigma that accompanies the individual in the course of growth and development. If a certain clinical symptom of Tourette syndrome persists in adults, it can have detrimental effects on emotional and functional burden, which can hinder both personal psychophysical wellbeing and social relationships, with significant implications also in terms of employment. To date there is no curative treatment for Tourette syndrome, although several treatments are recommended to relieve motor symptoms, including behavioural intervention and drugs, particularly α-2 adrenergic agonists and antipsychotics.8 Botulinum toxin has long been used to treat movement disorders, but despite its efficacy it has been poorly investigated in randomized controlled trials and it has not been approved by the FDA for most hyperkinetic disorders.12 It has been hypothesized that this neurotoxin is able to reduce Tourette syndrome symptoms by weakening muscles that produce tics.13 However, this Cochrane Review suggests that it is uncertain if this intervention is effective and safe for Tourette syndrome considering the very low quality of evidence. On the other hand, the latest AAN guidelines for treatment of chronic tic disorders suggest, with the lowest allowable recommendation level (level C), that physicians may use onabotulinum toxin A injection for treating older adolescents and adults with focal and disabling tics. However, the same guidelines strongly recommend that patients with Tourette syndrome are advised that the benefits of this intervention are temporary and may cause weakness and hypophonia.8 From a rehabilitation perspective, Tourette syndrome is a neurodevelopmental condition potentially resulting in heterogeneous impairments, activity limitations, and participation restrictions in different functioning domains. Although botulinum toxin injection is a long-established practice in the treatment of many disabling conditions, in light of the available evidence and recent guidelines on this topic the approach to Tourette syndrome must be interdisciplinary and person-centred, providing cognitive–behavioural, psychological, and pharmacological interventions where indicated. The author thanks Cochrane Rehabilitation and Cochrane Movement Disorders Group for reviewing the contents of the Cochrane Corner. The author has stated that he had no interests that could be perceived as posing a conflict or bias.

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