Abstract: Fourteen clinical trials, involving 721 participants, met the criteria for inclusion in the review. Thirteen studies compared a pharmaceutical treatment with placebo (or a low dose of the intervention), in heterogenous groups of degenerative cerebellar ataxias. Three compounds were studied in two trials each: a levorotatory form of 5-hydroxytryptophan (L-5HT), idebenone and thyrotropin-releasing hormone tartrate (TRH-T); each of the other compounds (riluzole, varenicline, buspirone, betamethasone, coenzyme Q10 with vitamin E, α-tocopheryl quinone and erythropoietin) were studied in one trial. The 14th trial, involving a mixed group of participants with spinocerebellar ataxia, compared the effectiveness of nonspecific physiotherapy and occupational therapy within an inpatient hospital setting to no treatment. No studies utilised traditional speech therapies. We defined the primary outcome measure in this review as the percentage change (improvement) in overall speech production immediately following completion of the intervention or later, measured by any validated speech assessment tool. None of the trials included speech as a primary outcome or examined speech using any validated speech assessment tool. Eleven studies reported speech outcomes derived from a subscale embedded within disease rating scales. The remaining three studies used alternative assessments to measure speech, including mean time to produce a standard sentence, a subjective rating of speech on a 14-point analogue scale, patient-reported assessment of the impact of dysarthria on activities of daily living and acoustic measures of syllable length. One study measured speech both subjectively as part of a disease rating scale and with further measures of speech timing. Three studies utilised the Short Form-36 Health Survey (SF-36) and one used the Child Health Questionnaire as measures of general quality of life. A further study utilised the Functional Independence Measure to assess functional health. Five studies reported statistically significant improvement on an overall disease rating scale in which a speech subscale was included. Only three of those studies provided specific data on speech performance; all were comparisons with placebo. Improvements in overall disease severity were observed with α-tocopheryl quinone; however, no significant changes were found on the speech subscale in a group of individuals with Friedreich ataxia. A statistically significant improvement in speech according to a speech disorders subscale was observed with betamethasone. Riluzole was found to have a statistically significant effect on speech in a group of participants with mixed hereditary, sporadic and unknown origin ataxias. No significant differences were observed between treatment and placebo in any other pharmaceutical study. A statistically significant improvement in functional independence occurred at the end of the treatment period in the rehabilitation study compared to the delayed treatment group but these effects were not present 12 to 24 weeks after treatment. Of the four studies that assessed quality of life, none found a significant effect. A variety of minor adverse events were reported for the 13 pharmaceutical therapies, including gastrointestinal side effects and nausea. Serious adverse effects were reported in two participants in one of the L-5HT trials (participants discontinued due to gastrointestinal effects), and in four participants (three taking idebenone, one taking placebo) in the idebenone studies. Serious adverse events with idebenone were gastrointestinal side effects and, in people with a previous history of these events, chest pain and idiopathic thrombocytopenic purpura. The rehabilitation study did not report any adverse events. We considered six studies to be at high risk of bias in some respect. We suspected inadequate blinding of participants or assessors in four studies and poor randomisation in a further two studies. There was a high risk of reporting bias in two studies and attrition bias in four studies. Only one study had a low risk of bias across all criteria. Taken together with other limitations of the studies relating to the validity of the measurement scales used, we downgraded the quality of the evidence for many of the outcomes to low or very low. There is insufficient and low or very low quality evidence from either RCTs or observational studies to determine the effectiveness of any treatment for speech disorder in any of the hereditary ataxia syndromes.

Plain-language summary: We searched widely for clinical trials and found 14 trials of treatments for speech problems in hereditary ataxias. The trials involved 721 participants. The duration of treatment was between two weeks and two years. Thirteen trials compared a medicine to a placebo and the 14th compared a mixed physiotherapy and occupational therapy treatment to no treatment. Ten different medicines were tested: L-hydroxytryptophan (L-5HT) (two studies), thyrotropin-releasing hormone (TRH) (two studies), varenicline, riluzole, idebenone (two studies), betamethasone, coenzyme Q10 with vitamin E, buspirone, ɑ-tocopheryl quinone and erythropoietin. We did not find any studies of traditional speech therapies. There were three ongoing trials. When planning the review, we decided to use the percentage change in speech production after treatment as our primary measure of whether treatments were effective. None of the studies measured speech in a way that allowed us to report this. Five studies reported improvement in overall disease severity but only two studies, of riluzole in various ataxias and betamethasone in ataxia telangiectasia, demonstrated improvement of speech production. It is difficult to say whether these improvements in speech might make a meaningful difference to patients. A variety of minor adverse events occurred with the medicines, including effects on the stomach and intestines, such as feeling sick. This kind of effect caused two people taking L-5HT to stop treatment. Another person experienced this effect while taking idebenone. Two more people taking idebenone experienced heart or autoimmune problems; however, they each had experienced those problems earlier in their life. None of the other studies found differences in speech performance on active treatment. All trials had some problems in conduct or design that could potentially affect the findings. Most of the included studies were small and looked at a mixed group of people with different forms of ataxia. The current evidence base is of low or very low quality and does not allow us to decide whether treatments for speech problems in the hereditary ataxia syndromes are effective. The evidence is up to date to October 2013.