Medical treatment of dyskinetic cerebral palsy: translation into practice

Dyskinesia, a non-specific term, generally refers to abnormal movements encompassing a variety of hyperkinetic movement disorder phenomenology such as chorea, dystonia, and stereotypy, among others. Dyskinetic cerebral palsy (CP) is heterogeneous and can be subclassified into dystonic, choreoathetoid, and mixed phenotypes. Spasticity commonly coexists as a comorbidity and adds complexity to the classification and treatment. In movement disorder practice, the therapeutic approach to dystonia and chorea is different. Most commonly employed oral pharmacological therapies in dystonia include anticholinergics, especially trihexyphenidyl, baclofen, and clonazepam. In contrast, medical treatment of chorea includes presynaptic dopamine depletors, especially vesicular monoamine transporter 2 (VMAT2) inhibitors such as tetrabenazine, and postsynaptic dopamine receptor blockers (or neuroleptics). The latter are generally less preferred by some due to the risk of tardive dyskinesia. Anticholinergics can exacerbate chorea and are thus generally avoided. Tetrabenazine is rarely used in dystonia except for tardive dystonia. Treatment of dyskinetic CP is complex, as dystonic and choreoathetoid components require different approaches. Subclassification to dystonic and choreoathetoid phenotypes will hopefully provide solutions for this clinical conundrum, but there remain several challenges. First, patients often have mixed phenotypes with variable degrees of both dystonia and choreoathetosis. This has partially been addressed by the Dyskinesia Impairment Scale, which includes both phenomenological components. Second, differentiating motor overflow of dystonia from choreoathetosis is frequently difficult and clinicians may cover treatments for both when the phenomenology is blurred. Third, co-existing spasticity further complicates the classification and treatment evaluation, as efficacy of some medications such as baclofen and diazepam can be confounded by improvement in spasticity component. The systematic review by Masson et al. demonstrates that the current evidence does not strongly suggest efficacy of any oral medications in dyskinetic CP. It is important not to misinterpret this result as a lack of efficacy. Despite its advantage in clinical practice, evidence-based medicine has some limitations, and the invaluable role of clinical experience and expert opinion should not be dismissed. According to a care pathway for oral medical treatment of dystonia in CP by American Academy of Cerebral Palsy and Developmental Medicine (AACPDM), experts recommend baclofen as first-line, and trihexyphenidyl as second-line (http://www.aacpdm.org/publications/care-pathways/dystonia). This contrasts with other dystonias where trihexyphenidyl is generally used as first-line, and may reflect commonly coexisting spasticity that confounds the treatment efficacy. Importantly, contradictory results of levodopa efficacy in dyskinetic CP were generally derived after exclusion of alternative diagnoses including dopa-responsive dystonia (DRD). In clinical practice, levodopa trials still have a crucial role diagnostic confirmation, since DRD is a ‘don’t-miss’ treatable disorder with expanding phenotypic spectrum. Lessons from dystonia provide some insights for future clinical trials. Regarding trihexyphenidyl, high dosage (after slow titration) and adequate duration of treatment (up to several weeks) may be required. Physicians should not be reluctant to titrate anticholinergics to a high dosage especially in the pediatric population, since children are known to tolerate side effects better than adults. Furthermore, benzodiazepines (especially clonazepam) have been used in dystonia, thus theoretically their use should not be limited only as muscle relaxants in spasticity. Nevertheless, evidence of benzodiazepine use in dyskinetic CP is limited. Lastly, assessment of functional, rather than only movement disorder, outcomes is a more holistic method to determine therapeutic efficacy. In summary, this article provides valuable lessons from the past trials including the issue of phenotypic variability in dyskinetic CP, the effect of confounding spasticity, limited number of participants, possible insufficient doses, and duration of therapies. We hope that learning from the past will improve design of clinical trials in the future.