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Treatment for speech disorder in Friedreich ataxia and other

hereditary ataxia syndromes (Review)
Vogel AP, Folker J, Poole ML
Vogel AP, Folker J, Poole ML.

Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.
Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD008953.
DOI: 10.1002/14651858.CD008953.pub2.
www.cochranelibrary.com
Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Trusted evidence.
Informed decisions.
Library Better health. Cochrane Database of Systematic Reviews
TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
SUMMARY OF FINDINGS.............................................................................................................................................................................. 4
BACKGROUND.............................................................................................................................................................................................. 22
OBJECTIVES.................................................................................................................................................................................................. 22
METHODS..................................................................................................................................................................................................... 22
Figure 1.................................................................................................................................................................................................. 25
RESULTS........................................................................................................................................................................................................ 27
Figure 2.................................................................................................................................................................................................. 28
DISCUSSION.................................................................................................................................................................................................. 37
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 38
ACKNOWLEDGEMENTS................................................................................................................................................................................ 39
REFERENCES................................................................................................................................................................................................ 40
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 43
APPENDICES................................................................................................................................................................................................. 61
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 65
DECLARATIONS OF INTEREST..................................................................................................................................................................... 65
SOURCES OF SUPPORT............................................................................................................................................................................... 65
DIFFERENCES BETWEEN PROTOCOL AND REVIEW.................................................................................................................................... 66
INDEX TERMS............................................................................................................................................................................................... 66
Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes (Review) i
Informed decisions.
[Intervention Review]
Treatment for speech disorder in Friedreich ataxia and other hereditary

ataxia syndromes
Adam P Vogel1, Joanne Folker2, Matthew L Poole1
1Speech Neuroscience Unit, University of Melbourne, Melbourne, Australia. 2School of Health and Rehabilitation Sciences, The
University of Queensland, Brisbane, Australia
Contact address: Adam P Vogel, Speech Neuroscience Unit, University of Melbourne, 550 Swanston Street, Parkville, Melbourne,
Victoria, 3010, Australia. vogela@unimelb.edu.au.
Editorial group: Cochrane Neuromuscular Group.

Publication status and date: New, published in Issue 10, 2014.
Citation: Vogel AP, Folker J, Poole ML. Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes.
Cochrane Database of Systematic Reviews 2014, Issue 10. Art. No.: CD008953. DOI: 10.1002/14651858.CD008953.pub2.
ABSTRACT
Background
Hereditary ataxia syndromes can result in significant speech impairment, a symptom thought to be responsive to treatment. The type
of speech impairment most commonly reported in hereditary ataxias is dysarthria. Dysarthria is a collective term referring to a group
of movement disorders affecting the muscular control of speech. Dysarthria affects the ability of individuals to communicate and to
participate in society. This in turn reduces quality of life. Given the harmful impact of speech disorder on a person's functioning, treatment
of speech impairment in these conditions is important and evidence-based interventions are needed.
Objectives
To assess the effects of interventions for speech disorder in adults and children with Friedreich ataxia and other hereditary ataxias.
Search methods
On 14 October 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, CINAHL
Plus, PsycINFO, Education Resources Information Center (ERIC), Linguistics and Language Behavior Abstracts (LLBA), Dissertation Abstracts
and trials registries. We checked all references in the identified trials to identify any additional published data.
Selection criteria
We considered for inclusion randomised controlled trials (RCTs) or quasi-RCTs that compared treatments for hereditary ataxias with no
treatment, placebo or another treatment or combination of treatments, where investigators measured speech production.
Data collection and analysis

Two review authors independently selected trials for inclusion, extracted data and assessed the risk of bias of included studies using
the standard methodological procedures expected by The Cochrane Collaboration. The review authors collected information on adverse
effects from included studies. We did not conduct a meta-analysis as no two studies utilised the same assessment procedures within the
same treatment.
Main results
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
Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes (Review) 1
Informed decisions.
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.
Authors' conclusions
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
Treatment for speech disorder in Friedreich ataxia and other hereditary ataxia syndromes (inherited disorders of movement co-
ordination)
Review question
We reviewed the evidence about the effects of treatment on speech difficulties in people with Friedreich ataxia and other hereditary ataxias.
Background
People with hereditary ataxia develop problems with co-ordinating movement, which becomes worse over time. There are a range of other
symptoms but this is the main feature of this group of diseases. Symptom onset is dependent on disease type and can begin in childhood
or adulthood. Some types of hereditary ataxia appear later in life, even in middle age or older. Friedreich ataxia (FRDA) is the most common
of the young onset hereditary ataxias.
Speech difficulties are a major feature of many of these disorders. People with ataxia often seek medical help because of slower speech,
slurred speech or because the voice sounds harsh, or more nasal. Such difficulties can affect how well a person is able to communicate
with friends, family and workmates.
Study characteristics
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
Informed decisions.
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.
Key results
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.
Conclusions
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.
SUMMARY OF FINDINGS
Summary of findings for the main comparison. Hydroxytryptophan versus placebo for speech disorder resulting from hereditary ataxias
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Hydroxytryptophan (L-5HT) for speech disorder resulting from hereditary ataxias
Patient or population: people with speech disorder resulting from hereditary ataxias
Settings: hospital
Intervention: L-5HT
Better health.
Informed decisions.
Trusted evidence.
Outcomes Illustrative comparative risks* (95% Relative No of Qual- Comments
CI) effect partici- ity of
(95% pants the evi-
Assumed risk Corresponding CI) (stud- dence
risk ies) (GRADE)
Placebo L-5HT
Short-term (within 1 month) percentage See comment See comment Not es- 0 See Not an outcome in these studies
change (improvement) in overall speech timable (0) com-
production ment
Short-term (within 1 month) change in iso- The mean short- The mean short- Not es- 4 ⊕⊝⊝⊝ Results from Trouillas 1995 and Wessel
lated movement, objective and subjective term (within 1 term (within 1 timable (Wessel very 1995 were not comparable due to differ-
measures of speech production month) change month) change 1995 3,4) low 4,5,6 ence in outcome measurement
Wessel 1995: Mean syllable duration during in isolated move- in isolated move-
rapid-syllable repetition task. Scale from: 1 to ment, objec- ment, objec- 19 No differences were observed after treat-
500. Shorter durations are better. Follow-up: tive and subjective and subjec- (Trouil- ment in either the placebo or L-5HT con-
10 months tive measures of tive measures of las 1995) ditions in either Trouillas 1995 or Wessel
speech produc- speech production 1995
Trouillas 1995: Mean time for producing a tion in the con- in the intervention
standard sentence. Shorter durations are bet- trol groups was a groups was
ter. Follow-up: 6 months 2 ms increase 0 ms higher (CI

in mean syllable not calculable)1
duration (Wessel (Wessel 1995)
1995)
0.5 s lower (0.9 s
0.2 s increase lower to 0.1 lower)
(Trouillas 1995) (Trouillas 1995)
Short-term (within 1 month) change in See comment See comment Not es- 0 See Not an outcome in Trouillas 1995 or Wes-
quality of life scores related to communica- timable (0) com- sel 1995
tion as measured by validated communica- ment
tion assessments
4
Longer-term (minimum 1 month) change in See comment See comment Not es- 0 See Not an outcome in Trouillas 1995 or Wes-
generic quality of life scores timable (0) com- sel 1995
ment
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Adverse effects (during the study) See comment See comment Not es- 65 See Minor gastrointestinal side effects in 8/39
timable (2 stud- com- L-5HT and 5/39 placebo participants in
ies) ment Wessel 1995 and 6/14 L-5HT and 2/12
placebo participants in Trouillas 1995. Da-
ta could not be pooled because Wessel
Better health.
Informed decisions.
Trusted evidence.
1995 did not break down results by condi-
tion
Longer-term burdens (minimum 1 month) See comment See comment Not es- 0 See Not an outcome in Trouillas 1995 or Wes-
(for example demands on caregivers, timable (0) com- sel 1995
frequency of tests and restrictions on ment
lifestyle)
Economic outcomes See comment See comment Not es- 0 See Not an outcome in Trouillas 1995 or Wes-
timable (0) com- sel 1995
ment
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the as-
sumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; L-5HT: L-hydroxytryptophan; RR: risk ratio
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1CI of estimate of effect was not calculable in Wessel 1995, as no measure of variance was reported for the change.
2Cross-over study design where the 4 participants each contributed 2 measurements (Wessel 1995).

3Only 4 of the original 19 participants with Friedreich ataxia completed the speech assessments during both arms of Wessel 1995, while only 19 of 26 participants completed
Trouillas 1995.
4Missing data from Friedreich ataxia group in Wessel 1995.
5The method of allocation and blinding is not clear in Trouillas 1995. Adverse effects within the treatment arm may reduce the success of blinding of investigators or participants.
6Mean duration of a standard sentence is an insensitive measure of dysarthria (Trouillas 1995).
Summary of findings 2. Thyrotropin-releasing hormone tartrate versus placebo for speech disorder resulting from hereditary ataxia
Thyrotropin-releasing hormone tartrate (TRH-T) for speech disorder resulting from hereditary ataxia
5
Patient or population: people with speech disorder resulting from hereditary ataxia
Settings: hospital
Intervention: TRH-T
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Outcomes Illustrative compar- Relative No of Qual- Comments
ative risks* (95% CI) effect partici- ity of
(95% pants the evi-
As- Corre- CI) (stud- dence
sumed spond- ies) (GRADE)
Better health.
Informed decisions.
Trusted evidence.
risk ing risk
Placebo TRH-T
Short-term (1 week) percentage change See See Not es- 0 See Not an outcome in Filla 1988 or Sobue 1983
(improvement) in overall speech produc- com- com- timable (0) com-
tion ment ment ment
Short-term (1 week) change in isolated See See Not es- 245 ⊕⊝⊝⊝ Raw data were not reported in either study investigating TRH-
movement, objective and subjective mea- com- com- timable (2 stud- very T. Improvements in speech were observed in both treatment
sures of speech production ment ment ies1) low 2,3,4 and placebo conditions
Inherited Ataxias Clinical Rating Scale
(IACRS)
Follow-up: mean 3.5 weeks
Short-term (1 week) change in quality of See See Not es- 0 See Not an outcome in Filla 1988 or Sobue 1983
life scores related to communication as com- com- timable (0) com-
measured by validated communication as- ment ment ment
sessments
Longer-term (minimum 1 month) change in See See Not es- 0 See Not an outcome in Filla 1988 or Sobue 1983
generic quality of life scores com- com- timable (0) com-
ment ment ment

Adverse effects (during study) See See Not es- 320 See Adverse effects included psycho-neurologic effects (e.g.
com- com- timable (2 stud- com- headache, dizziness and drowsiness), cardiovascular (e.g. hot
ment ment ies) ment feeling, flushing, palpitation and chest oppressed feeling),
gastrointestinal (e.g. nausea, vomiting and abdominal pain)
and other effects (e.g. urinary frequency, general malaise
and sweating) in 50/101 participants on 2 mg TRH, 35/92 par-
ticipants on 0.5 mg TRH and 20/97 participants on placebo
(Sobue 1983)
Filla 1988 reported 44 adverse effects for participants on

TRH-T, however did not report on adverse effects experienced
by participants on placebo
6
Longer-term burdens (minimum 1 month) See See Not es- 0 See Not an outcome in Filla 1988 or Sobue 1983
(for example demands on caregivers, fre- com- com- timable (0) com-
quency of tests, restrictions on lifestyle) ment ment ment
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Economic outcomes See See Not es- 0 See Not an outcome in Filla 1988 or Sobue 1983
com- com- timable (0) com-
ment ment ment
Better health.
Informed decisions.
Trusted evidence.
CI: confidence interval;RR: risk ratio; TRH-T: thyrotropin-releasing hormone tartrate

1 Filla 1988 (n = 31) utilised a cross-over design.

2Reported outcomes for speech do not include all participants (Sobue 1983).
3Speech was not a primary outcome measure, but a subscale on a disease severity measure (Filla 1988; Sobue 1983).
4Speech performance was evaluated via subjective clinician-derived measures of severity (Filla 1988; Sobue 1983).
Summary of findings 3. Varenicline versus placebo for speech disorder resulting from hereditary ataxia
Varenicline for speech disorder resulting from hereditary ataxia
Settings: hospital
Intervention: varenicline

Outcomes Illustrative comparative risks* (95% CI) Relative No of Qual- Comments
effect partici- ity of
Assumed risk Corresponding risk (95% pants the evi-
CI) (stud- dence
Placebo Varenicline ies) (GRADE)
Short-term (1 week) percentage change (im- See comment See comment Not es- 0 See Not an outcome in this
provement) in overall speech production timable (0) com- study
ment
7
Short-term (1 week) change in isolated The mean short-term The mean short-term (1 Not cal- 13 ⊕⊝⊝⊝ Speech did not significant-
movement, objective and subjective mea- (1 week) change in iso- week) change in isolated culable (1 study) very ly improve in the treat-
sures of speech production lated movement, ob- movement, objective and low ment or placebo condi-
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SARA. Scale from: 0 to 6. Higher scores indicate jective and subjective subjective measures of 2,3,4,5 tions
more severe speech disorder. measures of speech speech production in the in-
Follow-up: mean 56 days production in the con- tervention groups was
trol groups was a 0.06 greater decrease
a decrease of 0.39 (no measure of variance)1
Better health.
Informed decisions.
Trusted evidence.
Short-term (1 week) change in quality of life See comment See comment Not es- 0 See Not an outcome in this
scores related to communication as mea- timable (0) com- study
sured by validated communication assessment
ments
Longer-term (minimum 1 month) change in The mean longer-term The mean longer-term (min- Not cal- 13 ⊕⊝⊝⊝ Functional health did not
generic quality of life scores (minimum 1 month) imum 1 month) change in culable (1 study) very significantly improve in ei-
SF-36 change in generic generic quality of life scores low 2,5 ther condition
Follow-up: mean 56 days quality of life scores in in the intervention groups
the control groups was was
Scale of 0 to 100. Higher score reflects less dis- a decrease of 1.42 1.75 higher
ability (no measure of variance)1
Adverse effects (during study) See comment See comment Not es- 18 See 27 adverse effects were
timable (1 study) com- reported for the vareni-
ment cline group and 19 ad-
verse effects for the place-
bo group.
18 participants entered
the treatment phase (9 in
each group)
Longer-term burdens (minimum 1 month) See comment See comment Not es- 0 See Not an outcome in this
(for example, demands on caregivers, fre- timable (0) com- study

quency of tests, restrictions on lifestyle) ment
Economic outcomes See comment See comment Not es- 0 See Not an outcome in this
timable (0) com- study
ment
CI: confidence interval; RR: risk ratio; SARA: Scale for the Assessment and Rating of Ataxia; SF-36: Short Form 36 Health Survey

8
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1CI of estimate of effect not calculable as the variance of change was not reported.
2Only 5 participants completed the placebo arm and 8 completed the varenicline arm of the study. The placebo group had higher clinical severity scores and appeared on average
older compared to the varenicline group, possibly influencing their responsiveness to treatment (Filla 2012). The small sample size and lack of control for multiple comparisons
may also introduce imprecision and statistical error.
Better health.
Informed decisions.
Trusted evidence.
3Speech was not a primary outcome measure, but a subscale on a disease severity measure.
4Speech performance was evaluated via subjective clinician-derived measures of severity.
5Data were analysed for 9 participants in each group despite the large participant dropouts. The timing of these assessments was not stated. The second period of the experiment,
which was to include a cross-over component, was abandoned due to the high dropout rate observed in the initial period reported.
Summary of findings 4. Riluzole versus placebo for speech disorder resulting from hereditary ataxias
Riluzole for speech disorder resulting from hereditary ataxias
Settings: hospital
Intervention: riluzole

CI) (stud- dence
Placebo Riluzole ies) (GRADE)
Short-term (1 week) percentage change (im- See comment See comment Not es- 0 See Not an outcome in this study
provement) in overall speech production timable (0) com-
ment

Short-term (within 1 month) change in isolat- The mean short- The mean short-term Not cal- 38 ⊕⊕⊝⊝ Statistically significant difference be-
ed movement, objective and subjective mea- term (within 1 (within 1 month) culable (1 study) low 1,2 tween groups (P value < 0.001). Data
sures of speech production month) change change in isolated were not divided by type of ataxia
ICARS. Scale from: 0 to 8. Higher scores indicate in isolated move- movement, objective
more severe speech disorder. ment, objec- and subjective mea-
Follow-up: mean 8 weeks tive and subjec- sures of speech pro-
tive measures of duction in the inter-
speech produc- vention groups was
tion in the con-
trol groups was 0.79 lower (0.43 to
0.05 higher 1.15 lower)
9
Short-term (within 1 month) change in quali- See comment See comment Not es- 0 See Not an outcome in this study
ty of life scores related to communication as timable (0) com-
measured by validated communication assessment
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ments
Longer-term (minimum 1 month) change in See comment See comment Not es- 0 See Not an outcome in this study
generic quality of life scores timable (0) com-
ment
Better health.
Informed decisions.
Trusted evidence.
Adverse effects (during study) See comment See comment Not es- 38 See 4 adverse events occurred: 3 in the
timable (1 study) com- riluzole group and 1 in the placebo
ment group (N = 20 in each group). 2 par-
ticipants in the treatment arm were
found to have an increase in alanine
aminotransferase 1.5 times over the
normal limit
Longer-term burdens (minimum 1 month) (for See comment See comment Not es- 0 See Not an outcome in this study
example, demands on caregivers, frequency of timable (0) com-
tests, restrictions on lifestyle) ment
Economic outcomes See comment See comment Not es- 0 See Not an outcome in this study
timable (0) com-
ment
CI: confidence interval; ICARS: International Cooperative Ataxia Rating Scale; RR: risk ratio


1Speech was not the primary outcome measure, but a subscale on a disease severity rating scale.
2Speech was rated subjectively on scales of 'fluency of speech' and 'clarity of speech'.
Summary of findings 5. Idebenone versus placebo for speech disorder resulting from hereditary ataxias
Idebenone for speech disorder resulting from hereditary ataxias
10
Settings: hospital
Intervention: idebenone
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(95% pants the evi-
risk ing risk
Better health.
Informed decisions.
Trusted evidence.
Placebo Idebenone
Short-term (1 week) percentage See See Not es- 0 See Not an outcome in the two studies of idebenone
change (improvement) in overall com- com- timable (0) com-
speech production ment ment ment
Short-term (within 1 month) change See See Not es- 117 (2 very low Speech subscales were not reported separately from overall ICARS
in isolated movement, objective and com- com- timable studies) 1,2,3,4 or FARS scores in the 2 studies investigating idebenone
subjective measures of speech pro- ment ment
duction
ICARS, FARS
Follow-up: mean 6 months
Longer-term (minimum 1 month) See See Not es- 0 See Not an outcome in the 2 studies of idebenone
change in generic quality of life scores com- com- timable (0) com-
ment ment ment
Adverse effects (during study) See See Not es- 118 See Among the 118 participants in the 2 studies, 4 serious adverse
com- com- timable (2 stud- com- events were reported in participants taking idebenone. Only 1,
ment ment ies) ment neutropenia, was reported to be related to the study drug. There
were 200 non-serious adverse events in treatment groups and 58
in the placebo group in Di Prospero 2007, while 21 participants
in treatment groups and 10 placebo participants experienced ad-
verse events in Lynch 2010. The incidence of adverse events was

similar in treatment and placebo groups in both studies
Longer-term burdens (minimum 1 See See Not es- 0 See Not an outcome in the 2 studies of idebenone
month) (for example, demands on com- com- timable (0) com-
caregivers, frequency of tests, restric- ment ment ment
tions on lifestyle)
Economic outcomes See See Not es- 0 See Not an outcome in the 2 studies of idebenone
ment ment ment
11
CI: confidence interval; FARS: Friedreich Ataxia Rating Scale; ICARS: International Cooperative Ataxia Rating Scale; RR: risk ratio
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Informed decisions.
Trusted evidence.
1Investigators in Di Prospero 2007 implemented a second statistical analysis without non-symptomatic and non-ambulatory participants, with the rationale that this would
remove floor and ceiling effects caused by the tests used. This group was found to experience greater improvement from the drug.
2Speech was measured as subjective impression of investigator in both Di Prospero 2007 and Lynch 2010.
3Speech was not measured directly, but as part of a larger ataxia assessment scale in both Di Prospero 2007 and Lynch 2010.
4While Di Prospero 2007 found an improvement on the ICARS, Lynch 2010 did not identify improvements due to idebenone. This was despite Lynch 2010 using similar doses of
idebenone over the same timeframe as Di Prospero 2007. Lynch 2010 also excluded participants with ICARS scores lower than 10 and greater than 54 in order to identify the larger
improvements within this subgroup observed in Di Prospero 2007.
Summary of findings 6. Physiotherapy and occupational therapy versus placebo for speech disorder resulting from hereditary ataxias
Physiotherapy and occupational therapy for speech disorder resulting from hereditary ataxias
Settings: inpatient hospital rehabilitation
Intervention: physiotherapy and occupational therapy

CI) (stud- dence
Control Physiotherapy and occupation- ies) (GRADE)

al therapy
Short-term (1 week) percentage change See comment See comment Not es- 0 See Not an outcome in
(improvement) in overall speech produc- timable (0) com- this study
tion ment
Short-term (1 week) change in isolat- The mean short-term (1 The mean short-term (1 week) 42 ⊕⊝⊝⊝ No statistically sig-
ed movement, objective and subjective week) change in isolated change in isolated movement, (1 very nificant treatment
measures of speech production movement, objective and objective and subjective mea- study2) low 5,6 response was ob-
SARA. Scale from: 0 to 6. Higher scores indi- subjective measures of sures of speech production in the served
cate more severe speech disorder. speech production in the intervention groups was
Follow-up: 4 weeks1 control groups was
12
an increase of 0.1 0.2 lower (0.48 lower to 0.08
higher)
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Short-term (1 week) change in quality of The mean short-term (1 The mean short-term (1 week) 42 ⊕⊝⊝⊝ Significant improve-
life scores related to communication as week) change in quality of change in quality of life scores re- (1 very ment in total FIM
measured by validated communication life scores related to com- lated to communication as mea- study2) low 3,4 score immediate-
assessments munication as measured sured by validated communica- ly post intervention
Functional Independence Measure (total). by validated communication assessments in the interven- and at 4 weeks. No
Scale from: 0 to 126. Higher scores indicate tion assessments in the tion groups was significant effect for
less disability control groups was 1.4 higher treatment at 12 or 24
Better health.
Informed decisions.
Trusted evidence.
Follow-up: mean 4 weeks1 a decrease of 0.2 (0.57 to 2.23 higher) weeks post interven-
tion
Longer-term (minimum 1 month) change See comment See comment Not es- 0 See Not an outcome in
in generic quality of life scores timable (0) com- this study
ment
Adverse effects (during study) See comment See comment Not es- 42 See None reported
timable (1 study) com-
ment
Longer-term burdens (minimum 1 See comment See comment Not es- 0 See Not an outcome in
month) (for example, demands on care- timable (0) com- this study
givers, frequency of tests, restrictions on ment
lifestyle)
Economic outcomes See comment See comment Not es- 0 See Not an outcome in
timable (0) com- this study
ment
CI: confidence interval;FIM: Functional Independence Measure; RR: risk ratio; SARA: Scale for the Assessment and Rating of Ataxia

1Long-term follow-up was conducted at 12 to 24 weeks; however, all participants had completed the same treatment and were therefore not controlled after the initial 4-week
treatment or no treatment phase.
2Only the first 4 weeks of the study were randomised. Post intervention (at 12 to 24 weeks), assessments measured longer-term treatment effects as all participants completed
the same treatment.
3Ratings were based on subjective clinician-derived measures of severity.
13
4The speech subscale was not reported in long-term follow-up.
5Speech performance was evaluated via subjective clinician-derived measures of severity.
6Speech was not a primary outcome measure, but a subscale on a disease severity measure.
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Summary of findings 7. Betamethasone versus placebo for speech disorder resulting from hereditary ataxias
Betamethasone (BETA) for speech disorder resulting from hereditary ataxias
Better health.
Informed decisions.
Trusted evidence.
Settings: university
Intervention: betamethasone

CI) (stud- dence
Placebo BETA ies) (GRADE)
Short-term (1 week) percentage change (improve- See comment See comment Not es- 0 See Not an outcome in this study
ment) in overall speech production timable (0) com-
ment
Short-term (within 1 month) change in isolated The median The median short- Not es- 13 ⊕⊕⊕⊝ Statistically significant differ-
movement, objective and subjective measures of short-term (with- term (within 1 timable (1 cross- moder- ence between groups (P value =
speech production in 1 month) month) change in over ate 1 0.02)
ICARS. Scale from: 0 to 8. Higher scores indicate more change in isolat- isolated movement, study)
severe disorder. Follow-up: mean 30 days ed movement, objective and sub- Changes were reported as me-
objective and jective measures of dians
subjective mea- speech production
sures of speech in the intervention
production in the groups was
control groups a 0.1 greater reduc-

was tion
a reduction of (0.5 lower to 2.5 low-
0.5 er))2
Short-term (within 1 month) change in quality of See comment See comment Not es- 0 See Not an outcome in this study
life scores related to communication as measured timable (0) com-
by validated communication assessments ment
Longer-term (minimum 1 month) change in generic See comment See comment Not cal- 0 See Data not presented. No differ-
quality of life scores culable (0) com- ence reported between groups
Child Health Questionnaires ment
Follow-up: mean 30 days
14
Adverse effects (during study) See comment See comment Not es- 13 See Mild adverse effects included
timable (1 cross- com- asthenia (1 participant), mood
over ment swings (1 participant), moon
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study) face (8 participants), increased
body weight (12 participants)
Longer-term burdens (minimum 1 month) (for ex- See comment See comment Not es- 0 See Not an outcome in this study
ample, demands on caregivers, frequency of tests, timable (0) com-
restrictions on lifestyle) ment
Better health.
Informed decisions.
Trusted evidence.
Economic outcomes See comment See comment Not es- 0 See Not an outcome in this study
timable (0) com-
ment
BETA: betamethasone; CI: confidence interval;ICARS: International Cooperative Ataxia Rating Scale; RR: risk ratio

1Speech disorder was measured on a subjective, clinician-derived severity rating scale.

2The CI was not calculable in Zannolli 2012 as the variance of change was not reported.
Summary of findings 8. High-dose versus low-dose coenzyme Q10 and vitamin E for speech disorder resulting from hereditary ataxia
High-dose versus low-dose coenzyme Q10 (CoQ10) and vitamin E for speech disorder resulting from hereditary ataxia

Settings: hospital
Intervention: CoQ10 and vitamin E (high dose versus low dose)

CI) (stud- dence
CoQ10 and vitamin E CoQ10 and vitamin E ies) (GRADE)
(low dose) (high dose)
15
Short-term (1 week) percentage change (improve- See comment See comment Not es- 0 See Not an outcome in this
ment) in overall speech production timable (0) com- study
ment
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Short-term (within 1 month) change in isolated The mean short-term The mean short-term Not es- 43 ⊕⊕⊝⊝ No statistically signif-
movement, objective and subjective measures of (within 1 month) (within 1 month) change timable (1 study) low 1,2 icant difference was
speech production change in isolated in isolated movement, observed between
Cooper 2008 reported 3 speech measures: movement, objective objective and subjective groups for any speech
and subjective mea- measures of speech pro- measure
ICARS speech subscale. Scale from: 0 to 8. Higher
Better health.
Informed decisions.
Trusted evidence.
sures of speech production in the high- dose
scores indicate greater clinical severity duction in the low- group was
dose group was ICARS speech subscale:
Syllable repetition (number of repetitions of "pata"
ICARS speech sub- 0.03 higher (0.16 lower to
per 10 seconds). Higher repetitions represent lesser
scale: a decrease of 0.22 higher)
speech impairment
0.05
Syllable repetition: 0.5
Time taken (seconds) to read a standard passage.
Syllable repetition: a higher (0.03 lower to 1.03
Higher scores represent greater speech impairment
decrease of 0.6 higher)
Follow-up: mean 2 years
Standard passage: an Standard passage: 2.3
increase of 0.7 higher
Short-term (within 1 month) change in quality of See comment See comment Not es- 0 See Not an outcome in this
life scores related to communication as measured timable (0) com- study
by validated communication assessments ment
Longer-term (minimum 1 month) change in gener- See comment See comment Not es- 0 See Not an outcome in this
ic quality of life scores timable (0) com- study
ment
Adverse effects (during study) See comment See comment Not es- 50 See No major adverse
timable (1 study) com- events Minor effects
ment included increased
bowel frequency (1

participant, high-dose
group) and prolonged
nausea (1 participant,
low-dose group)
Longer-term burdens (minimum 1 month) (for See comment See comment Not es- 0 See Not an outcome in this
example, demands on caregivers, frequency of timable (0) com- study
tests, restrictions on lifestyle) ment
16
Economic outcomes See comment See comment Not es- 0 See Not an outcome in this
timable (0) com- study
ment
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Cochrane
CI: confidence interval; CoQ10 : coenzyme Q10; ICARS: International Cooperative Ataxia Rating Scale; RR: risk ratio
Better health.
Informed decisions.
Trusted evidence.
1Results are reported for both the RCT (no significant results) and for a comparison of the treated groups with a cross-sectional data set, which was not adequately described.
2The primary outcome measure was based on a subjective measure of speech quality.
Summary of findings 9. Buspirone versus placebo for speech disorder in Friedreich ataxia and other hereditary ataxias
Buspirone for speech disorder in Friedreich ataxia and other hereditary ataxias
Patient or population: people with speech disorder in Friedreich ataxia and other hereditary ataxias
Settings: hospital
Intervention: buspirone
Outcomes Illustrative compara- Relative No of Qual- Comments

tive risks* (95% CI) effect partici- ity of
(95% pants the evi-
sumed sponding ies) (GRADE)
risk risk

Placebo Buspirone
Short-term (1 week) percentage change (improvement) in See See com- Not es- 0 See Not an outcome in this study
overall speech production comment timable (0) com-
ment ment
Short-term (within 1 month) change in isolated movement, See See com- Not es- 19 ⊕⊕⊝⊝ Speech subscales were not reported
objective and subjective measures of speech production comment timable (1 cross- low 1,2,3 separately from overall ICARS scores. No
ICARS. Follow-up: mean 12 weeks ment over difference between groups
study)
17
Short-term (within 1 month) change in quality of life scores See See com- Not es- 0 See Not an outcome in this study
related to communication as measured by validated commu- com- ment timable (0) com-
nication assessments ment ment
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Longer-term (minimum 1 month) change in generic quality of See See com- Not es- 0 See Not an outcome in this study
life scores comment timable (0) com-
ment ment
Adverse effects (during study) See See com- Not es- 19 See Minor adverse events included dizziness
Better health.
Informed decisions.
Trusted evidence.
comment timable (1 cross- com- in 5 participants (4 buspirone, 1 place-
ment over ment bo) and drowsiness in 4 participants (3
study) buspirone and 1 placebo)
Longer-term burdens (minimum 1 month) (for example, See See com- Not es- 0 See Not an outcome in this study
demands on caregivers, frequency of tests, restrictions on comment timable (0) com-
lifestyle) ment ment
Economic outcomes See See com- Not es- 0 See Not an outcome in this study
comment timable (0) com-
ment ment
CI: confidence interval; ICARS: International Cooperative Ataxia Rating Scale; RR: risk ratio

1Speech was measured on a subjective scale.

2The speech subscale of ICARS was not reported separately from the total score.
3Genetically confirmed Friedreich ataxia and SCA were analysed in same group as idiopathic ataxias. Data were not presented for genetically confirmed ataxias only.
Summary of findings 10. α-tocopheryl quinone versus placebo for speech disorder resulting from hereditary ataxia
α-tocopheryl quinone for speech disorder resulting from hereditary ataxia
Settings: hospital
Intervention: α-tocopheryl quinone
18
Outcomes Illustrative comparative risks* (95% Relative No of Qual- Comments
CI) effect partici- ity of
(95% pants the evi-
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Cochrane
Assumed risk Corresponding risk CI) (stud- dence
ies) (GRADE)
Placebo α-tocopheryl
quinone
Short-term (1 week) percentage change (improve- See comment See comment Not es- 0 See Not an outcome in Lynch 2012
Better health.
Informed decisions.
Trusted evidence.
ment) in overall speech production timable (0) com-
ment
Short-term (within 1 month) change in isolated See comment See comment Not es- 0 See Not an outcome in Lynch 2012
movement, objective and subjective measures of timable (0) com-
speech production ment
Short-term (within 1 month) change in quality of life See comment See comment Not es- 0 See Not an outcome in Lynch 2012
scores related to communication as measured by val- timable (0) com-
idated communication assessments ment
Longer-term (minimum 1 month) change in generic The mean The mean longer- Not cal- 19 ⊕⊕⊕⊝ No statistically significant dif-
quality of life scores longer-term term (minimum 1 culable (1 study) moder- ference between groups. Da-
SF-36 scale from: 0 to 100. Higher score indicate less (minimum 1 month) change in ate 1 ta presented for placebo and
disability. Follow-up: mean 28 days month) change generic quality of life high-dose (0.75 g twice daily)
in generic quali- scores in the inter- treatment arms only
ty of life scores vention groups was
in the control 3.27 lower
groups was (7.79 lower to 1.25
an increase of higher)
3.26
Adverse effects (during study) See comment See comment Not es- 31 See No severe drug-related adverse
timable (1 study) com- events occurred. Minor ad-

ment verse events were found equal-
ly across the treatment arms
Longer-term burdens (minimum 1 month) (for exam- See comment See comment Not es- 0 See Not an outcome in Lynch 2012
ple, demands on caregivers, frequency of tests, re- timable (0) com-
strictions on lifestyle) ment
Economic outcomes See comment See comment Not es- 0 See Not an outcome in Lynch 2012
timable (0) com-
ment
19
CI: confidence interval; RR: risk ratio; SF-36: Short Form 36 Health Survey
Library
Cochrane
Better health.
Informed decisions.
Trusted evidence.
1The method of randomisation is not clear and did not completely match the three groups. The placebo group had higher clinical severity scores.
2Speech was measured using a subjective clinical impression.
Summary of findings 11. Erythropoietin versus placebo for speech disorder in Friedreich ataxia and other hereditary ataxias
Recombinant human erythropoietin (rhuEPO) for speech disorder in Friedreich ataxia and other hereditary ataxias
Patient or population: people with speech disorder in Friedreich ataxia and other hereditary ataxias
Settings: hospital
Intervention: rhuEPO

(95% pants the evi-
risk ing risk
Placebo rhuEPO
Short-term (1 week) percentage change (improvement) in overall See See Not es- 0 See Not an outcome in this study

speech production com- com- timable (0) com-
ment ment ment
Short-term (within 1 month) change in isolated movement, objective See See Not cal- 16 ⊕⊕⊝⊝ Speech subscales were not re-
and subjective measures of speech production com- com- culable (1 study) low 1,2 ported separately to overall SARA
SARA. Scale from: 0 to 48. Follow-up: mean 6 months ment ment scores. No difference between
groups
Short-term (within 1 month) change in quality of life scores related See See Not es- 0 See Not an outcome in this study
to communication as measured by validated communication assess- com- com- timable (0) com-
ments ment ment ment
20
Longer-term (minimum 1 month) change in generic quality of life See See Not cal- 16 ⊕⊕⊝⊝ No difference between groups
scores com- com- culable (1 study) low 3,4
SF-36. Scale from 0 to 100. Higher scores indicate less disability. Fol- ment ment
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low-up: mean 6 months
Adverse effects (during study) See See Not es- 16 See No serious adverse events. 3
com- com- timable (1 study) com- participants had sideropenic
ment ment ment anaemia (2 rhuEPO group and 1
placebo group)
Better health.
Informed decisions.
Trusted evidence.
Longer-term burdens (minimum 1 month) (for example, demands on See See Not es- 0 See Not an outcome in this study
caregivers, frequency of tests, restrictions on lifestyle) com- com- timable (0) com-
ment ment ment
Economic outcomes See See Not es- 0 See Not an outcome in this study
ment ment ment
CI: confidence interval; rhuEPO: recombinant human erythropoietin; RR: risk ratio; SARA: Scale for the Assessment and Rating of Ataxia; SF-36: Short Form 36 Health Sur-
vey

1Speech was not measured directly but as part of an overall clinical severity scale.
2Speech was measured on a subjective, clinician-rated, scale.
3Unclear randomisation, allocation concealment and blinding.

4Magnitude of change is not reported.
21
Informed decisions.
BACKGROUND How the intervention might work

Ataxias are neurological conditions in which muscle co- The effectiveness of an intervention can best be conceptualised
ordination is impaired. Friedreich ataxia, an autosomal recessive using the International Classification of Functioning, Disability
neurodegenerative disorder, is the most common hereditary ataxia. and Health (ICFDH) (WHO 2001). At an impairment level, this
It affects approximately 1 in 40,000 people (Delatycki 2000). means improving the capacity of people with a hereditary
Several other known autosomal dominant ataxias (for example, ataxia to communicate orally. This can be achieved in speech
spinocerebellar ataxias (SCAs)) and recessive hereditary ataxias can therapy by enhancing the production of sounds and words,
also affect speech. In many hereditary ataxias, speech difficulties by improving breath support for speech, maintaining adequate
have been documented as a common outcome of disease levels of intelligibility and, where possible, restoring the person's
progression (Rosen 2012), typically manifesting as dysarthria speech to pre-morbid levels. At an activity and participation level,
(slurred speech). In the case of Friedreich ataxia (Folker 2010) and interventions might increase a person's ability to participate in
SCA (Schalling 2007), individuals often present with a reduced rate the many social and professional activities for which effective
of speech, vocal instability and imprecise consonants. Dysarthria communication skills are needed. Finally, changes can be made
affects the ability to communicate and participate in society, at an environmental level to improve communication outcomes
and reduces quality of life. Given the harmful impact of speech for the person with speech difficulties (for example, by educating
difficulties on a person's functioning, a strong body of evidence is communication partners on effective strategies). Improvement in
required on which to base the treatment of speech impairment in these three domains could enable people with hereditary ataxias
these conditions. to participate in society more actively and maintain personal and
professional relationships.
Description of the condition
Why it is important to do this review
The major clinical features of Friedreich ataxia include progressive
ataxia (100%), dysarthria (95%), scoliosis (78%), cardiomyopathy Dysarthria is a primary feature of Friedreich ataxia, with estimates
(65%), diabetes mellitus (8%) and foot deformity (74%) (Delatycki of prevalence ranging from 91% (Dürr 1996) to 100% (Folker 2010;
1999). Onset generally occurs in childhood at an average age of 10 Schöls 1997). A study in Friedreich ataxia by Harding 1981 showed
years, with the individual losing the ability to walk at an average dysarthria to be present in all participants 10 years after onset of the
age of 19 years. Life expectancy is markedly reduced. The many condition, suggesting that speech disorder is an inevitable outcome
recognised SCAs vary in their clinical presentation and age of onset, of disease progression. Speech disorder is also a key component
and some are known to influence speech function (Schalling 2007). of other hereditary ataxias including the SCAs (Schalling 2007);
The prevalence of speech disorder in SCA is not yet known. A however, prevalence rates are not yet known. The likely presence
number of rare autosomal recessive hereditary ataxias also exist, of speech impairment in all individuals with a hereditary ataxia
where little is known about the clinical features relating to speech. necessitates the development of effective and proven therapies for
Speech impairment in Friedreich ataxia and SCA varies depending this aspect of these disorders.
on a number of factors, for example the severity of other clinical
features and the stage of disease progression. At the impairment OBJECTIVES
level, dysarthria arises from impaired respiratory, phonatory
To assess the effects of interventions for speech disorder in adults
and articulatory subsystems underlying speech production (Duffy
and children with Friedreich ataxia and other hereditary ataxias.
2013). Perceptually, dysarthria is often characterised by a reduced
vocal pitch or uncontrolled variation in pitch, a slower rate of METHODS
speech, imprecise production of sounds (slurred speech) and
reduced intelligibility. Deleterious consequences can also go Criteria for considering studies for this review
beyond the physiological impairment level and lead to activity
limitation (for example, avoiding use of the telephone) or the Types of studies
misperception by others that the person is cognitively impaired We considered all randomised controlled trials (RCTs) and quasi-
(Gibilisco 2013). Difficulties can be influenced by environmental RCTs for inclusion. Quasi-RCTs are studies in which participants
factors (for example, background noise) (Hartelius 2007). Limited are allocated to intervention groups by methods that are not
data exist on the speech profiles of recessive hereditary ataxias truly random, such as alternate days, date of birth or case record
other than Friedreich ataxia. number.
Description of the intervention Types of participants
This review focuses on the effects of treatments, including speech We considered studies with participants of any age, sex, ethnicity,
therapy or pharmaceutical therapies, for people with hereditary stage of illness and any degree of illness severity. We included only
ataxias. Speech therapy may take the form of instrumental studies in which participants had a genetically confirmed diagnosis
intervention, traditional drill-based therapy techniques or a of a hereditary ataxia, unless the studies were conducted prior
combination of both. Typically, pharmaceutical treatments are to the discovery of the disease-specific gene (i.e. Dürr 1996 for
designed to alter the natural course of the disease itself. In Friedreich ataxia and Orr 1993 for SCA1).
Friedreich ataxia, for example, medications may be designed to
reduce muscle tremors and spasms, treat cardiac issues or increase Types of interventions
levels of frataxin (reduced expression of the protein frataxin is the
Interventions in four categories of therapy to improve speech,
cause of Friedreich ataxia).
based on intervention types described in Morgan 2008, compared
Informed decisions.
to no treatment, placebo or another treatment or combination 1980 to October 2013), CINAHL Plus (January 1937 to October
of treatments were considered for inclusion in the review. The 2013), PsycINFO (January 1806 to October 2013), Education
categories of therapy were as follows. Resources Information Center (ERIC) (January 1966 to October
2013), Linguistics and Language Behavior Abstracts (LLBA) (1973 to
1. Non-instrumental intervention: intervention using traditional October 2013) and Dissertation Abstracts (1980 to October 2013).
drill exercises with auditory feedback (perceptual) as the We also searched ClinicalTrials.gov (www.clinicaltrials.gov/) and
primary means of feedback. For example, exercises of the lips the World Health Organization International Clinical Trials Registry
or tongue to increase the rate, strength, range or co-ordination Platform (ICTRP) (www.who.int/ictrp/en/) for ongoing trials.
of the musculature supporting articulation; drill breathing
exercises to increase respiratory/breath support for speech; and The detailed search strategies are in the appendices:
voicing drills to increase the loudness of phonation. Neuromuscular Disease Group Specialized Register (Appendix 1),
2. Instrumental approaches utilising biofeedback: interventions CENTRAL (Appendix 2), MEDLINE (Appendix 3), EMBASE (Appendix
that use some form of instrumentation and that provide 4), CINAHL Plus (Appendix 5), PsycINFO (Appendix 6), ERIC Dialog
visual or other forms of biofeedback in addition to auditory (Appendix 7), ERIC ProQuest (Appendix 8), LLBA (Appendix 9),
feedback. For example, electropalatography; kinematics; and Dissertation Abstracts (Appendix 10), ClinicalTrials.gov (Appendix
visual biofeedback acoustic treatment. 11), and ICTRP (Appendix 12).
3. Pharmaceutical treatments with speech function as a primary,
Searching other resources
secondary or other outcome measure.
4. Any other intervention or combination of interventions. We scanned conference abstracts for relevant studies. We checked
all references in the identified trials to identify any additional
We included interventions if they were administered for a minimum published data.
of one week and a maximum of 12 months.
We requested information from authors of potentially relevant
Types of outcome measures trials. We requested information on unpublished data from authors
of five published studies (Assadi 2007; Di Prospero 2007; Filla 1988;
We considered both standardised and nonstandardised speech-
Lynch 2010; Mariotti 2009), but no additional data were available.
specific outcome measures. Outcome measures that were not
We made contact with experts and information groups in the
speech-specific acted as secondary assessment tools.
areas of linguistics and speech therapy; however, we identified no
Primary outcomes additional trials.
Our primary outcome measure was the percentage change Data collection and analysis
(improvement) in overall speech production immediately following
Selection of studies
completion of the intervention or later, measured by any validated
speech assessment tool). Two authors (AV and JF) independently screened titles and
abstracts to exclude reports that were obviously irrelevant. In cases
Secondary outcomes of uncertainty we evaluated the full-text article. Two review authors
Secondary outcomes were the following. (AV and JF) evaluated the full-text article of potentially eligible
studies. In the event of disagreement over inclusion of a particular
1. Change in isolated movement, objective and subjective paper, AV, JF and MLP reached a consensus after re-assessing the
measures of speech production (for example, acoustic analysis inclusion criteria together. We selected studies without limitation
of nasality; articulation; laryngeal function; respiratory function; as to language.
and oral motor function), within one month post intervention.
Data extraction and management
2. Change in quality of life scores related to communication,
measured by validated communication assessments such as the Two authors (AV and JF) performed data extraction and
Voice Handicap Index (ordinal variables), within one month post independently entered data onto a data extraction form.
intervention. Discrepancies would have been resolved by the third author (MP)
3. Generic quality of life measures (for example, Short Form-36 but this was not necessary. Two authors checked these data, AV
Health Survey (SF-36)), a minimum of one month post entered them into Review Manager (RevMan) and JF checked the
intervention. data entry.
4. Adverse effects (during the study).
The data extraction form included the following items.
5. Burdens (for example, demands on caregivers, frequency of
tests and restrictions on lifestyle), a minimum of one month post 1. General information: published/unpublished, title, authors,
intervention. reference/source, contact address, country, language of
6. Economic outcomes (for example, cost and resource use). publication, year of publication.
2. Trial characteristics: design, duration of follow-up, method of
Search methods for identification of studies randomisation, allocation concealment, blinding (participants,
Electronic searches people administering treatment and outcome assessor).
3. Participants: age, sex and any other recorded baseline
On 14 October 2013, we searched the Cochrane Neuromuscular characteristics, inclusion and exclusion criteria, total number
Disease Group Specialized Register, CENTRAL (2013, Issue 9), of participants, number in each group, disease severity,
MEDLINE (January 1966 to September 2013), EMBASE (January withdrawals and losses to follow-up (reasons and description).
Informed decisions.
4. Intervention(s) and outcome(s): placebo or control Systematic Reviews of Interventions (Higgins 2011), and presented
interventions included, type of speech therapy, drug judgements for each included trial in the 'Risk of bias' summary
dosage regimen, duration, frequency, interval, comparison (Figure 1). We assessed trials in the following domains: sequence
intervention(s), co-treatment(s), the number and type of generation, allocation concealment, blinding (participants and
adverse events, other outcomes reported in the trial. outcome assessors), incomplete outcome data (participant losses
and use of intention-to-treat (ITT) analysis), selective outcome
We resolved differences in data extraction by consensus, and reporting and other sources of bias. We then made a judgement of
by referring back to the original article. Where necessary, we high, low or unclear risk of bias for each domain. We would have
requested further information from the authors of the primary consulted the third author in the event of disagreement or resolved
studies. disagreements by discussion, or both.
Assessment of risk of bias in included studies
AV and JF independently assessed all included studies for risk of
bias. We graded the items according to the Cochrane Handbook for
Informed decisions.
Figure 1. 'Risk of bias 'summary: review authors' judgements about each risk of bias item for each included study.
Key: green (+) = low risk of bias; yellow (?) = unclear risk of bias; red (-) = high risk of bias.
Informed decisions.
Measures of treatment effect We had planned to evaluate funnel plot asymmetry visually and use
formal tests for funnel plot asymmetry. If the plots had suggested
Measures of treatment effect for primary outcome measures
that treatment effects may not be sampled from a symmetric
relied on the outcome measures provided by the study authors
distribution, as assumed by the random-effects model, we would
including: improvements in isolated sound, single word, sentence
have performed further meta-analyses using a fixed-effect model.
or conversation level productions. We would have analysed data
using the Cochrane statistical package Review Manager (RevMan) 5 Data synthesis
(RevMan 2014), had suitable data been available.
Meta-analysis was not possible and we therefore reported the
In the protocol for this review we stated that "For dichotomous data results of the trials narratively. Eight out of 11 treatments included
we will derive risk ratios (RR) and 95% confidence intervals (CIs) in this review were assessed in only one study. Meta-analyses of the
for each outcome. For continuous variables we will calculate mean studies involving the same intervention were not possible because
differences and 95% CIs for each outcome. We will use a fixed-effect they used different outcome measures or lacked data relating to
model to calculate pooled estimates and their 95% CIs, however, speech outcomes.
if the model yields large standard errors (i.e. the studies are not
homogenous), a random-effects model will be considered" (Vogel 'Summary of findings' table
2011b); however, no data were available for analysis. If studies are We included a 'Summary of findings' table, incorporating our key
available in future, to enable the combination of studies measuring primary and secondary outcome measures as follows.
the same outcome using different measurement tools, we will
summarise continuous data using standardised mean differences. 1. Short-term percentage change (improvement) in overall speech
We considered that binary outcomes were likely to be common production.
in early reports within the field (e.g. improved outcome versus no 2. Short-term change in isolated movement, objective and
change or worse). We planned to analyse such data by calculation subjective measures of speech production.
of the RR with a 95% CI.
3. Short-term change in quality of life scores related to
Unit of analysis issues communication as measured by validated communication
assessments.
For cross-over designs, the effect of conditioning represents a 4. Longer-term (minimum one month) change in generic quality of
potential source of bias if the training period precedes no training. life scores.
For this reason, if a difference in treatment effects and its standard
5. Adverse effects (during study).
error had been available from a cross-over trial, we would have
combined results with those of parallel-group studies using the 6. Economic outcomes.
generic inverse variance (GIV) facility in RevMan. In the absence of
The table also included information about trial characteristics
these data we would have analysed only the first arm of the study.
(for example, design and duration of follow-up), and participants.
Dealing with missing data We assessed the quality of evidence for each outcome for each
comparison using Grading of Recommendations Assessment,
One review author (AV) contacted primary investigators for Development and Evaluation (GRADE) criteria: study limitations,
assistance and information in cases where data were missing within consistency of effect, imprecision, indirectness and publication
published studies. bias. We used methods and recommendations described in
Section 8.5 and Chapter 12 of the Cochrane Handbook for
Assessment of heterogeneity Systematic Reviews of Interventions (Higgins 2011), and prepared
We did not conduct a meta-analysis as no two studies employed the tables using GRADEpro software (GRADEpro 2008). We included
the same assessments for any one drug. Lynch 2010 and Di information in footnotes to justify our decisions to down- or up-
Prospero 2007 both compared the effect of idebenone or placebo grade the quality of evidence.
in participants with Friedreich ataxia using the International
Cooperative Ataxia Rating Scale (ICARS); however, data on the Subgroup analysis and investigation of heterogeneity
speech subscales of the disease rating scale were not available. In reference to participant characteristics, we planned to undertake
subgroup analysis by modus of inheritance and causative gene or
If data had been available we planned to assess consistency of chromosomal locus, type of ataxia and the severity of dysarthria.
results using the I2 statistic for heterogeneity (Higgins 2011). I2 is
a quantity describing approximately the proportion of variation in We would have also considered heterogeneity in reference to
point estimates that is due to heterogeneity of a sample rather study design and implementation characteristics, including, but
than error in sampling of the population. For values greater than not limited to, methods of recruitment and randomisation and
50%, we would have examined forest plots for differences between methods of implementing therapy. However, no such analyses were
trials which could explain the heterogeneity. We would have used possible.
a test of homogeneity to determine whether the heterogeneity was
genuine. In the event of too few studies being available to make this Sensitivity analysis
test feasible, we would have applied a random-effects model. If studies had been suitable for meta-analysis, we would have
Assessment of reporting biases used sensitivity analysis to assess the robustness of the overall
findings by examining the impact of study quality; for example, lack
There were insufficient studies to investigate publication bias and of allocation concealment or high rates of loss to follow-up, the
other reporting biases using funnel plots. impact of missing data or the impact of imputations, and the rigour
Informed decisions.
of eligibility criteria employed in the study. We would have also Results of the search
evaluated the possibility of one or more large studies dominating
The search conducted up until October 2013 identified 494 records
the results.
and we identified a further nine records from reference lists. Table 1
The methods for this systematic review were prespecified in the reports the number of studies retrieved from each search strategy.
protocol (Vogel 2011b). We have listed deviations from protocol in After duplicates were removed, 425 records remained from which
Differences between protocol and review. we retrieved 56 papers for further examination. After screening the
full text of the 56 selected papers for eligibility, 14 papers were
RESULTS not relevant, 25 papers were excluded for methodological reasons
and 14 studies met the inclusion criteria (Assadi 2007; Cooper
Description of studies 2008; Di Prospero 2007; Filla 1988; Lynch 2010; Lynch 2012; Mariotti
2009; Miyai 2012; Ristori 2010; Sobue 1983; Trouillas 1995; Wessel
See Characteristics of excluded studies and Characteristics of 1995; Zannolli 2012; Zesiewicz 2012). We identified three ongoing
included studies. studies (EUCTR 2009-016317-20-IT; EUCTR 2012-005312-26-DE;
Schulz 2009), which are described in Characteristics of ongoing
studies. A flow diagram of the study selection process is presented
in Figure 2.
Informed decisions.
Figure 2. Study flow diagram.
Informed decisions.
Figure 2. (Continued)
Table 1
Database Period searched Date searched Number of hits
Cochrane Neuromuscular Disease Group Up to 15 October 2013 15 October 2013 0

Specialized Register
CENTRAL Up to 14 October 2013 14 October 2013 25
MEDLINE 1966 to October 2013 14 October 2013 96
EMBASE 1980 to October 2013 14 October 2013 75
CINAHL 1937 to October 2013 14 October 2013 35
PsycINFO 1806 to October 2013 14 October 2013 95
ERIC 1966 to October 2013 14 October 2013 31
LLBA 1973 to October 2013 15 October 2013 59
Dissertation Abstracts 1980 to October 2013 15 October 2013 62
Clinical Trial Registries Up to 15 October 2013 15 October 2013 16
Additional records from reference lists - - 9

of relevant studies
Included studies Setting

We included 14 studies in the qualitative analysis and these are Trials were carried out in Europe, Japan and the USA. Filla 1988,
described in the Characteristics of included studies section. Mariotti 2009 and Ristori 2010 were performed in Italy, Wessel 1995
in Germany, Cooper 2008 in the UK, and Assadi 2007, Zesiewicz
Design 2012, Lynch 2010, Lynch 2012 and Di Prospero 2007 in the USA,
Assadi 2007, Filla 1988, Wessel 1995 and Zannolli 2012 used a all in outpatient settings. Trouillas 1995 was conducted across
double-blind, placebo-controlled, cross-over design. Miyai 2012 12 outpatient settings in France. Interventions in Miyai 2012 and
employed a single-blinded, randomised design. Di Prospero 2007, Sobue 1983 were administered in an inpatient setting in Japan.
Lynch 2010, Lynch 2012, Mariotti 2009, Ristori 2010, Sobue 1983, Zannolli 2012 was a multicentre study that took place in six Italian
Trouillas 1995 and Zesiewicz 2012 were double-blind, placebo- universities.
controlled, randomised, parallel-group studies. Cooper 2008 was
Participants
a double-blind, randomised trial with a low-dose group as
comparison. There were 721 participants in the 14 included studies. Thirty-
nine participants with degenerative cerebellar ataxias, including
Informed decisions.
Friedreich ataxia (19), olivopontocerebellar atrophy (7) and first and last third of the phase and a tapered dose during the
cerebellar atrophy (13), were recruited to Wessel 1995. We only middle 10 days of each phase. Cooper 2008 was a comparison of
included data on the Friedreich ataxia group in this review high- and low-dose coenzyme Q10 (CoQ10) plus vitamin E (600 mg
as the aetiology of disease for the cerebellar atrophy and CoQ10 and 2100 IU vitamin E per day versus 30 mg CoQ10 and 4 IU
olivopontocerebellar atrophy participants was unclear. Sixteen vitamin E per day). Lynch 2012 administered both high doses (750
participants with Friedreich ataxia and 14 participants with mg/day) and low doses (510 mg/day) of α-tocopheryl quinone and
various degenerative ataxias (prior to the discovery of disease- compared each to placebo over a period of 28 days. Mariotti 2009
specific genotypes) completed Filla 1988. Miyai 2012 recruited was a comparison of recombinant human erythropoietin (rhuEPO)
42 participants with pure cerebellar degeneration; they included versus placebo over a period of 24 weeks. Dosages of rhuEPO were
20 people with SCA6 (genetically confirmed), six people with 20,000 IU every three weeks for nine weeks (visits one to three),
SCA31 and 16 participants with idiopathic cerebellar ataxia. Twenty 40,000 IU every three weeks for nine weeks (visits four to six) and
participants with SCA3 were recruited to Zesiewicz 2012 and 13 40,000 IU every two weeks for six weeks (visits seven to nine). Assadi
completed the study. Ristori 2010 included 40 participants with 2007 treated participants with buspirone HCl 30 mg twice daily or
ataxia from a range of aetiologies (eight SCA, eight Friedreich placebo for 12 weeks.
ataxia, one fragile X tremor/ataxia syndrome, 10 sporadic ataxia
and 13 ataxic syndromes of unknown origin). Performance on the Outcomes
speech subscale was not broken down by diagnosis. Individuals
with genetically confirmed Friedreich ataxia were recruited in the Wessel 1995 employed syllable repetition rates as an index of motor
following studies: Cooper 2008 (50 participants), Di Prospero 2007 speech performance. The extended duration of each phase of the
(48 participants), Lynch 2010 (70 participants), Lynch 2012 (31 study (10 months) makes it difficult to separate the effect of the
participants) and Mariotti 2009 (16 participants). Trouillas 1995 drug from the influence of disease progression. Every two months,
recruited 26 participants clinically diagnosed with Friedreich ataxia for six months after the start of treatment, Trouillas 1995 measured
(not genetically confirmed). Sobue 1983 initially recruited 290 speech by timing participants as they produced a standard
participants with spinocerebellar degeneration (SCD) and reported sentence. Assadi 2007, Cooper 2008, Di Prospero 2007, Filla 1988,
on the speech outcomes of 214 participants with predominantly Lynch 2010, Lynch 2012, Mariotti 2009, Miyai 2012, Ristori 2010,
cerebellar forms of SCD at all time points. Zannolli 2012 recruited Zannolli 2012 and Zesiewicz 2012 all employed subjective clinician-
13 participants with ataxia telangiectasia. Assadi 2007 involved derived measures of severity to evaluate speech production, which
20 individuals with ataxia of various aetiologies, including four was measured at various time points between 12 weeks and two
with Friedreich ataxia, nine with SCA, one with dentatorubral- years. Speech subscales of severity scales were analysed separately
pallidoluysian atrophy (DRPLA) and six with idiopathic ataxia. from the total score in Cooper 2008, Lynch 2012, Ristori 2010 and
Zannolli 2012. Cooper 2008 also assessed speech by measuring the
Interventions timing of a standard passage and syllable repetition. Sobue 1983
measured speech on a 14-point dysarthria scale as rated by the
Wessel 1995 administered the levorotatory form of neurologist.
hydroxytryptophan (L-5HT) orally in a dose of 1000 mg/day.
Each treatment phase, with L-5HT or placebo, lasted 10 months, Lynch 2012, Mariotti 2009, Miyai 2012, Zannolli 2012 and Zesiewicz
after which the participants crossed over to the other phase. 2012 included functional health as an outcome measure.
Investigating treatment effects over 10 months in a progressive
neurodegenerative disease makes delineation of treatment versus Excluded studies
placebo effects difficult. In Trouillas 1995, L-5HT was administered The reasons for exclusion of the 25 excluded studies are given in
for a period of six months. Dosage was dependent upon participant Characteristics of excluded studies. The predominant reason for
weight, being 200 mg/day to 600 mg/day during the first month exclusion was that the studies were not RCTs or quasi-RCTs. We
and 300 mg/day to 900 mg/day for the remaining five months. Filla contacted the authors of five RCTs for additional information.
1988 administered a daily dose of 2 mg and 4 mg of thyrotropin-
releasing hormone (TRH) tartrate or placebo intramuscularly, each Risk of bias in included studies
over a period of one month, in an ABCB design. In Sobue 1983,
the three treatment arms received either TRH tartrate 0.5 mg, For details of our 'Risk of bias' assessments see Figure 1.
TRH tartrate 2 mg or placebo over a period of two weeks. The
nonpharmaceutical trial, Miyai 2012, studied behavioural therapy Allocation
with a delayed intervention (no treatment) versus an immediate All studies randomly allocated participants to either treatment or
intervention paradigm. The report describes the intervention as a placebo (or no treatment in the delayed treatment arm of Miyai
mix of occupational therapy and physiotherapy sessions delivered 2012). The method of random selection was not clear in seven trials
every week day and for one hour on the weekend over four (Assadi 2007; Filla 1988; Mariotti 2009; Sobue 1983; Trouillas 1995;
weeks. In Zesiewicz 2012, participants' response to varenicline Wessel 1995; Zannolli 2012). The block randomisation and small
(Chantrix) (four weeks for titration and four weeks at a dose of sample size within Zesiewicz 2012 might have prevented equal
1 mg twice daily) was compared to the response to placebo over distribution of age and disease severity between the trial arms.
56 days. Ristori 2010 compared riluzole (two 50 mg tablets daily) The method of randomisation was not clear in Lynch 2012 and the
and placebo over eight weeks. Di Prospero 2007 and Lynch 2010 placebo group appears to have had a more severe mean clinical
compared various doses of idebenone with placebo over a period of rating. As a result we considered both these trials as at high risk of
six months. Betamethasone was compared with placebo in Zannolli bias. The method of allocation concealment was not clear in eight
2012, a cross-over study with two 30-day phases. The participants studies (Assadi 2007; Filla 1988; Lynch 2012; Mariotti 2009; Sobue
were given a full dose of betamethasone (0.1 mg/kg/day) for the
Informed decisions.
1983; Trouillas 1995; Wessel 1995; Zannolli 2012), but at low risk of not addressed. Three out of 13 participants from Zannolli 2012
bias in the rest of the included studies. were excluded from the per protocol analysis; however, statistical
analyses were provided for the ITT group. Of the 50 participants
Blinding in Cooper 2008, four withdrew from the high-dose group and
We judged blinding of participants in Wessel 1995 and Miyai 2012 three withdrew from the low-dose group. One participant in the
to be at high risk of bias. Wessel 1995 did not state whether high-dose treatment arm of Lynch 2012 discontinued treatment
there was blinding for the speech outcomes or whether the due to a protocol violation. One of the 20 participants in Assadi
same individual both assessed (recorded) and analysed speech. 2007 withdrew, having moved away from the treatment site. All
In addition, common adverse events, such as the gastrointestinal participants completed the Lynch 2010 and Mariotti 2009 studies
side effects seen with L-5HT in doses of 900 mg to 1000 mg orally according to the protocol.
per day, potentially undermine blinding. Eleven included studies
Selective reporting
assessed speech perceptually (subjectively) via clinician-derived
measures of severity. When speech assessments are conducted The primary outcome related to speech (syllable duration in ms)
within standardised clinical assessment protocols, information in Wessel 1995 was reported for a small selection of the Friedreich
collected as part of the clinical assessment is potentially able to ataxia group. Mean group scores and standard deviations were
influence judgements about speech function. Assessment of this reported. It is unclear if any additional outcomes were analysed
nature is susceptible to assessor bias and low levels of reliability. but not reported. Improvements in ataxic symptoms in Sobue 1983
The investigators who performed Miyai 2012 were reportedly were statistically tested using comparisons of the frequency of
blinded to the group allocation; however, the additional effects of participants in each treatment arm who either improved by at
inpatient stay and treatment regime were not clearly described. least one point on the 14-point scale or by at least two points on
Data from Trouillas 1995 are at a high risk of detection bias due to the 14-point scale. These methods make interpretation of clinical
the experience of adverse effects in the treatment arm. Blinding of significance difficult. We considered both these studies at high
outcome assessment may have been undermined in Sobue 1983, risk of bias from selective reporting. We considered two studies at
as it is not clear whether clinicians who assessed the safety of unclear risk of bias (Di Prospero 2007; Zesiewicz 2012). The report
the treatment also rated its efficacy. The method of blinding of of Zesiewicz 2012 does not state the timing of assessments. The
participants and assessors is not clear in Assadi 2007 and Mariotti second planned period of the experiment, which was to include a
2009. The blinding of investigators is also unclear in Zannolli 2012 cross-over component, was abandoned due to the high dropout
and Lynch 2012, although participants were adequately blinded. rate observed in the initial period. All outcomes were reported in Di
There is a low risk of both performance and detection bias in Cooper Prospero 2007; however, two statistical analyses were completed,
2008, Di Prospero 2007, Filla 1988, Lynch 2010, Ristori 2010 and based on the hypothesis that the second would remove floor and
Zesiewicz 2012. ceiling effects arising from the nature of the assessments used.
All assessments were reported in Ristori 2010, but the study did
Incomplete outcome data not report on results grouped by aetiology of ataxic symptoms.
Four studies were at high risk of attrition bias (Sobue 1983; All planned outcomes were reported in Assadi 2007, Cooper 2008,
Trouillas 1995; Wessel 1995; Zesiewicz 2012). Wessel 1995 reported Filla 1988, Lynch 2010, Lynch 2012, Mariotti 2009, Miyai 2012, Ristori
a limited data set (four out of 19 potential participants) for the 2010, Trouillas 1995 and Zannolli 2012.
only relevant subgroup (Friedreich ataxia). The reasons for these
Other potential sources of bias
dropouts were not addressed. Only five of the 10 participants
completed the placebo arm and eight of the 10 completed We judged other potential sources of bias (such as bias related
the varenicline arm of Zesiewicz 2012. Despite these dropouts, to the study design, analysis used or some other problem) as
data from nine participants in each group were included in the unclear for Filla 1988. We assessed Miyai 2012 as at high risk of
outcome description. Seven out of 26 participants did not complete bias in this category as the participants were treated in an inpatient
Trouillas 1995, two of whom withdrew due to adverse effects of setting within a hospital and may have been exposed to additional
the treatment. Six out of 220 participants with a predominantly therapeutic care during their stay. Any clinical discrepancies
cerebellar form of spinocerebellar degeneration in Sobue 1983 between comparison groups may influence group responsiveness
dropped out of the study. One participant did not complete to treatment. A failure to control for multiple comparisons can also
Miyai 2012 due to death. Filla 1988 reported one dropout in introduce error into statistical outcomes. Cooper 2008 reported the
the Friedreich ataxia group; we considered the risk of bias to results of both a randomised trial and a comparison of a cross-
be unclear. One participant from each of the experimental and sectional data set of untreated patients. The clinical details of this
control groups of Ristori 2010 withdrew consent prior to receiving cross-sectional data set were not described and we considered
riluzole or placebo and were therefore removed from the analysis. the risk of other bias to be unclear in this study. We identified no
One participant from Di Prospero 2007 on low-dose idebenone additional sources of bias in the 11 other trials (Assadi 2007; Di
withdrew due to illness prior to follow-up assessments, and we Prospero 2007; Lynch 2010; Lynch 2012; Mariotti 2009; Ristori 2010;
assessed the risk of bias as unclear. Two more participants were Sobue 1983; Trouillas 1995; Wessel 1995; Zannolli 2012; Zesiewicz
later removed as they had started rehabilitation during the trial. 2012).
Results of ataxic symptom visual analogue scales were reported
for only 218 participants who were classified with a diagnosis of Effects of interventions
a predominantly cerebellar form of SCD. At the conclusion of the
See: Summary of findings for the main comparison
trial, investigator-rated speech outcomes were reported for 214
Hydroxytryptophan versus placebo for speech disorder resulting
participants and participant-rated speech outcomes were reported
from hereditary ataxias; Summary of findings 2 Thyrotropin-
for 210 participants. The reasons for these reduced numbers are
releasing hormone tartrate versus placebo for speech disorder
Informed decisions.
resulting from hereditary ataxia; Summary of findings 3 the report did not provide a measure of variance of the change
Varenicline versus placebo for speech disorder resulting from following treatment.
hereditary ataxia; Summary of findings 4 Riluzole versus placebo
for speech disorder resulting from hereditary ataxias; Summary of Change in quality of life scores related to communication within one
month post intervention
findings 5 Idebenone versus placebo for speech disorder resulting
from hereditary ataxias; Summary of findings 6 Physiotherapy and Not reported.
occupational therapy versus placebo for speech disorder resulting
from hereditary ataxias; Summary of findings 7 Betamethasone Generic quality of life measures a minimum of one month post
versus placebo for speech disorder resulting from hereditary intervention
ataxias; Summary of findings 8 High-dose versus low-dose Not reported.
coenzyme Q10 and vitamin E for speech disorder resulting from
hereditary ataxia; Summary of findings 9 Buspirone versus Adverse effects
placebo for speech disorder in Friedreich ataxia and other Wessel 1995 (19 participants) reported minor gastrointestinal
hereditary ataxias; Summary of findings 10 α-tocopheryl quinone adverse effects in eight participants on L-5HT. Five participants
versus placebo for speech disorder resulting from hereditary ataxia; who received the placebo treatment complained of minor
Summary of findings 11 Erythropoietin versus placebo for speech gastrointestinal side effects. A risk ratio (RR) was not calculable as
disorder in Friedreich ataxia and other hereditary ataxias data were provided for all participants and not broken down by type
of disorder.
Hydroxytryptophan (L-5HT) versus placebo
Two studies compared L-5HT to placebo in participants with Trouillas 1995 (19 participants) reported minor gastrointestinal side
degenerative cerebellar disorders (Trouillas 1995; Wessel 1995). See effects in six participants on L-5HT and two participants from the
Characteristics of included studies and Summary of findings for the control group. Two of those participants on L-5HT left the study as
main comparison. a result of the adverse effects.
Burdens
Primary outcome: Percentage change (improvement) in overall
speech production immediately following completion of the Not reported.
intervention or later, measured by any validated speech
assessment tool Economic outcomes
Not reported. Not reported.
Secondary outcomes Thyrotropin-releasing hormone tartrate (TRH-T) versus

placebo
Change in isolated movement, objective and subjective measures of
speech production within one month post intervention Two studies compared TRH-T versus placebo in participants with
degenerative cerebellar disorders (Filla 1988; Sobue 1983). See
Wessel 1995 measured repetition rates for syllables as an index
Characteristics of included studies and Summary of findings 2.
of motor speech performance. The participants were asked to
produce chains of consonant-vowel syllables at maximum speed. Primary outcome: Percentage change (improvement) in overall
The three syllables /pa/, /ta/ and /ka/, involving movements of speech production immediately following completion of the
three different articulators, were used. Each task was performed intervention or later, measured by any validated speech
twice in the course of a more comprehensive articulation protocol, assessment tool
resulting in a total of six repetition tasks. Mean syllable durations
were calculated from smoothed sound pressure level contours of Not reported.
the speech wave. The lowest value that was obtained throughout
the six tasks, that is, each participant's optimum performance, Secondary outcomes
was used as the dependent variable. Syllable length was not Change in isolated movement, objective and subjective measures of
significantly different between the L-5HT and placebo conditions, speech production within one month post intervention
with a 2 ms (standard deviation range of 38 ms to 73 ms) increase
Filla 1988 employed a subjective rating (on a scale of zero to
in syllable duration in both groups. This analysis was based on only
four) of speech impairment based on clinical impression during
four of 19 participants with Friedreich ataxia.
administration of the Inherited Ataxias Clinical Rating Scale (IACRS).
Trouillas 1995 examined the rate of speech production among 19 We requested data on speech performance from the study authors,
participants by measuring the time required to produce a standard but data were not available. The report did not describe specific
sentence. The mean time for the treatment arm reduced by 0.3 data on speech changes; however, repeated measures ANOVA (n =
s and the mean time for the control arm increased by 0.2 s. This 30, F = 4.69, df = 4,116, P value < 0.001) showed significant changes
difference was not statistically significant. There was no meaningful between speech ratings before and after treatment with TRH-T.
difference between groups. The Neuman-Keuls method was used to identify sample means
that were statistically significantly different between groups and
Meta-analysis of the two studies was not possible due to time points. Significant differences were observed on both 2 mg
the heterogeneity of outcome measures. Results are provided of TRH (at two months P value < 0.05) and 4 mg of TRH (at four
in parallel in Summary of findings for the main comparison. months P value < 0.01) as well as the placebo condition at four
Confidence intervals (CIs) were not calculable in Wessel 1995, as months (P value < 0.05). Raw or summative data on speech were
Informed decisions.
not provided. No longer-term outcomes were described beyond the Varenicline versus placebo
washout period of the compound.
One study compared varenicline versus placebo in participants
Sobue 1983 reported results of investigator-rated speech with spinocerebellar ataxia (SCA) type 3 (Zesiewicz 2012). See
assessment and participant-rated impact of dysarthria on activities Characteristics of included studies and Summary of findings 3.
of daily living (ADL) for a subset of participants (n = 214) with
a predominantly cerebellar form of SCD. Statistical tests of the
speech production immediately following completion of the
symptoms of SCD were based on the numbers of participants in
each treatment arm who recorded improvements either greater
assessment tool
than one point or greater than two points on a 14-point scale. Data
from the investigator-rated scales showed statistically significantly Not reported.
differences across placebo, 0.5 mg of TRH-T and 2 mg of TRH-
T after one and two weeks of treatment respectively. Statistically Secondary outcomes
significant differences were not observed on either measure one Change in isolated movement, objective and subjective measures of
week after treatment concluded. Participant ratings of the impact speech production within one month post intervention
of dysarthria on ADL were not statistically significantly different on
any dose or placebo at any stage of the trial. Subjective rating of speech impairment based on clinical
impression formed during administration of the Scale for the Rating
The two studies investigating TRH-T provided neither raw data nor and Assessment of Ataxia (SARA). The SARA contains a subscale
measures of variance, therefore CI could not be calculated. focusing on speech function (a scale of zero to six where the
lower value indicates an improvement). Speech did not statistically
Change in quality of life scores related to communication within one significantly improve (n = 13, P value = 0.11) in either condition on
month post intervention the speech subscale of the SARA. The control group demonstrated
Not reported. a mean decrease of 0.39 on the speech subscale of the SARA and
the intervention group had a mean decrease of 0.45. CIs could not
Generic quality of life measures a minimum of one month post be calculated as variance in change was not reported.
intervention
Change in quality of life scores related to communication within one
Not reported. month post intervention
Adverse effects Not reported.
Filla 1988 (30 participants) reported a combination of adverse Generic quality of life measures a minimum of one month post
effects on the TRH-T treatment: nausea (18), vomiting (three), intervention
hot flushes (eight), sweating (three), headaches (four), dizziness
(four), palpitations (one) and urgent micturition (three). The Functional health and wellbeing was assessed using the SF-36. No
number of adverse effects was not reported for participants statistically significant improvement in functional health occurred
taking the placebo. All adverse effects occurred immediately after in either condition, with a 0.33 mean increase in the varenicline
administration of the drug and lasted a few minutes. A risk ratio condition and a 1.42 mean decrease in the placebo condition (n =
(RR) was not calculable as studies provided data on the number 13).
of adverse effects, not the number of participants experiencing Adverse effects
adverse effects.
The treatment and placebo arms contained nine participants
Sobue 1983 (256 participants) reported 50 adverse effects each. In the varenicline arm, six participants reported nausea,
among 101 participants on 2 mg TRH-T, including 14 psycho- one vomiting, one constipation, one disturbed sleep, one fatigue,
neurologic effects (e.g. headache, dizziness, drowsiness), 14 two vivid dreams, one irritability, one auditory hallucinations,
cardiovascular effects (e.g. hot feeling, flushing, palpitation, one spasticity, one increased stiffness in lower extremities, one
chest oppressed feeling), 28 gastrointestinal effects (e.g. nausea, increased dizziness, one increased tremor, two tingling in legs, one
vomiting, abdominal pain) and 20 other effects (e.g. urinary increased imbalance, one dizziness, one shaky legs, one leg cramps,
frequency, general malaise, sweating). Of the 92 participants one shivering, one blotchy feet and one cold feet. Two participants
on 0.5 mg TRH-T, 35 experienced adverse effects (four psycho- receiving varenicline decreased their dosage during the trial
neurologic, 12 cardiovascular, 29 gastrointestinal, 13 other) and because of adverse events. In total there were 27 reported adverse
20/97 participants on placebo experienced adverse effects (eight effects for the varenicline group and 19 reported adverse effects in
psycho-neurologic, nine cardiovascular, two gastrointestinal, six the placebo group, including one serious case of urosepsis. Four
other). Two participants experienced severe adverse effects (not participants in the placebo condition discontinued the study: one
described) but were able to continue the treatment. for urosepsis, one for muscle pain and two for noncompliance. One
participant in the varenicline group discontinued the study because
Burdens
of auditory hallucinations, which were later attributed to a sleep
Not reported. disorder. A RR was not calculable as the study provided data on
the number of adverse effects, but not the number of participants
Economic outcomes experiencing adverse effects in total.
Not reported. Burdens
Not reported.
Informed decisions.
Economic outcomes idebenone with placebo. See Characteristics of included studies

Not reported. and Summary of findings 5.
Riluzole versus placebo Primary outcome: Percentage change (improvement) in overall

speech production immediately following completion of the
One study compared riluzole versus placebo in a group of people intervention or later, measured by any validated speech
with mixed hereditary ataxias (Ristori 2010). See Characteristics of assessment tool
included studies and Summary of findings 4.
Not reported.
speech production immediately following completion of the Secondary outcomes
intervention or later, measured by any validated speech Change in isolated movement, objective and subjective measures of
assessment tool speech production within one month post intervention
Not reported. Di Prospero 2007 measured speech subjectively on a subscale of the

ICARS. A Jonckheere trend test on all participants who completed
Secondary outcomes the study (n = 47) revealed a statistically significant improvement in
Change in isolated movement, objective and subjective measures of overall ICARS scores, with the authors reporting that eye movement
speech production within one month post intervention and speech subsections were responsible for the majority of
observed variance. A subgroup of participants not including non-
The subjective rating of speech impairment was based on a symptomatic and non-ambulatory participants also revealed a
clinical impression formed during administration of the dysarthria statistically significant difference in overall ICARS scores on both
component of the International Cooperative Ataxia Rating Scale Jonckheere and ANCOVA statistical tests. The estimated difference
(ICARS) (scale zero to eight): speech statistically significantly in the change in ICARS score for the subset of participants was
improved in the riluzole condition (n = 38). The mean change in the 1.99 (95% CI -3.57 to 7.54) for the low-dose group (11 participants),
ICARS dysarthria subscale was -0.74 (standard deviation (SD) 0.81) 6.24 (95% CI 1.60 to 10.89) for the intermediate-dose group (13
versus 0.05 (SD 0.40) in the placebo group (P value < 0.001). Data participants) and 7.76 (95% CI 2.96 to 12.56) for the high-dose group
were provided for the participants as a whole and not by disease (12 participants). Speech subscales were not reported separately
type. from overall ICARS scores.
We requested additional data on speech performance from the By contrast, Lynch 2010 found no statistically significant differences
study authors, but data were not available. between idebenone and placebo groups in scores on the ICARS
or Friedreich Ataxia Rating Scale (FARS) (n = 70). Improvements
month post intervention (reductions) in mean ICARS scores for each group were -2.8
(standard error of the mean (SEM) 1.07) for placebo (n = 24), -4.3
Not reported. (SEM 1.22) for the 450/900 mg dose (n = 22) and -2.8 (SEM 1.43) for
the 1350/2250 mg dose (n = 24).
Generic quality of life measures a minimum of one month post
intervention
We requested data on speech performance from the respective
Not reported. study authors, but data were not available. We were therefore
unable to report measures of change.
Adverse effects
In the riluzole arm (20 participants), two participants were found month post intervention
to have an increase in alanine aminotransferase, a measure of liver
health (1.5 times above normal), and one participant presented Not reported.
with transient vertigo. In total there were three reported adverse
effects for the riluzole group and one reported adverse effect intervention
(transient vertigo) in the placebo group (20 participants). A RR
was not calculable as only one adverse event was observed in the Not reported.
placebo group.
Adverse effects
Burdens There were 200 adverse effects reported in the treatment
Not reported. groups and 58 in the placebo group of Di Prospero 2007 (48
participants). Two adverse events were serious enough to result
Economic outcomes in hospitalisation. One serious adverse event involved chest pain
Not reported. and occurred in the placebo group. The second event involved
nausea, vomiting and dehydration, which occurred in the low-
Idebenone versus placebo dose idebenone group three weeks after the completion of the
trial and was judged to be unrelated to the study medication. Only
Two studies compared idebenone versus placebo in participants one adverse event was thought to be related to the study drug.
with Friedreich ataxia (Di Prospero 2007; Lynch 2010). Di Prospero This was a case of neutropenia in a male participant in the high-
2007 compared low, intermediate and high doses of idebenone dose idebenone group. The neutropenia occurred after six months
with placebo and Lynch 2010 compared low and high doses of of treatment and resolved within a week of discontinuation of
Informed decisions.
idebenone. Statistical analysis revealed no statistically significant observed between baseline, post intervention and four-week post
difference in the incidence of adverse events between the four intervention scores on the total FIM and FIM motor scores, with a
groups. mean 1.2 (SE 0.3) increase in the treatment condition and a mean
0.2 (SE 0.3) decrease in the no treatment condition on the total FIM
Lynch 2010 (70 participants) reported two serious adverse at four weeks (MD 1.40, 95% CI 0.57 to 2.23) and a mean 1.1 (SE
events. One participant reported chest pain unrelated to 0.3) increase with treatment and a mean 0.1 (SE 0.3) decrease with
cardiac involvement and another experienced idiopathic placebo on the motor FIM at four weeks (MD 1.20, 95% CI 0.37 to
thrombocytopenic purpura; however, both participants had a prior 2.03).
history of the respective condition. Both incidents spontaneously
resolved while the participants were still taking study medication Adverse effects
and the events were considered unrelated to treatment. Less None reported. One participant died at week 17 (after the
serious adverse effects occurred at a comparable rate in idebenone randomised period of the study) from cerebral haemorrhage. This
and placebo groups; except for gastrointestinal tract irritations event was not reported as a consequence of the intervention.
which were more frequent in the high-dose idebenone group,
though this difference was not statistically significant. Adverse Burdens
events affected 14 participants in the high-dose treatment group,
seven participants in the low-dose group and 10 participants in the Not reported.
placebo group. Economic outcomes
Burdens Not reported.
Not reported. Betamethasone (BETA) versus placebo
Economic outcomes One study compared BETA (betamethasone disodium phosphate)
Not reported. with placebo in participants with ataxia telangiectasia, in a
randomised, double-blind, placebo-controlled, cross-over trial
Physiotherapy and occupational therapy versus no treatment (Zannolli 2012). See Characteristics of included studies and
Summary of findings 7.
One study compared physiotherapy and occupational therapy
versus no (delayed) treatment in participants with SCA6 and SCA31 Primary outcome: Percentage change (improvement) in overall
(and idiopathic SCA) (Miyai 2012). See Characteristics of included speech production immediately following completion of the
studies and Summary of findings 6. intervention or later, measured by any validated speech
assessment tool
speech production immediately following completion of the Not reported.
assessment tool Secondary outcomes
Not reported. Change in isolated movement, objective and subjective measures of

speech production within one month post intervention
Secondary outcomes Zannolli 2012 measured speech using a subscale of the ICARS and
Change in isolated movement, objective and subjective measures of compared BETA and placebo treatments with baseline. The median
speech production within one month post intervention reduction in severity on this subscale was one point greater with
BETA than the median reduction for placebo, within the intention-
Miyai 2012 assessed speech using a subjective rating based on to-treat (ITT) population (MD -1, 95% CI -2.5 to -0.5, n = 13).
clinical impression during administration of the SARA. The SARA
contains a subscale focusing on speech function (the subscale Change in quality of life scores related to communication within one
ranges from zero to six, where the lower value indicates an month post intervention
improvement). A mean decrease of 0.1 (standard error (SE) 0.1) on
Not reported.
the speech subscale was observed in the intervention group and a
mean increase of 0.1 (SE 0.1) was observed in the control group after Generic quality of life measures a minimum of one month post
treatment (four weeks); neither change was statistically significant; intervention
the between-group mean difference (MD) was -0.20 (95% CI -0.48 to
0.08). The analysis was based on the results of all 42 participants No significant difference was identified using quality of life
who were recruited. measures (Child Health Questionnaire) (n = 10). The magnitude of
change was not reported.
month post intervention Adverse effects
Not reported. One participant in Zannolli 2012 (total of 13 enrolled participants)

experienced asthenia during drug tapering, which did not require
Generic quality of life measures a minimum of one month post medical intervention. One further participant experienced mild
intervention mood swings and depressed attitude. Moon face was present
Miyai 2012 assessed functional independence using the Functional in eight participants on BETA. Small increases in body weight
Independence Measure (FIM). Significant differences were
Informed decisions.
occurred in 12 participants on BETA and four participants on with increased bowel frequency (high-dose group) and another
placebo. participant with prolonged nausea (low-dose group).
Burdens Burdens
Economic outcomes Economic outcomes
Coenzyme Q10 (CoQ10) and vitamin E in high dose and low Buspirone versus placebo
dose Assadi 2007 compared buspirone with placebo in participants
Cooper 2008 compared high and low doses of CoQ10 and vitamin with a variety of hereditary and idiopathic SCAs in a randomised,
E in participants with genetically confirmed Friedreich ataxia, in double-blind, placebo-controlled trial. See Characteristics of
a double-blind, randomised trial. See Characteristics of included included studies and Summary of findings 9.
studies and Summary of findings 8.
Primary outcome: Percentage change (improvement) in overall speech production immediately following completion of the
speech production immediately following completion of the intervention or later, measured by any validated speech
intervention or later, measured by any validated speech assessment tool
assessment tool Not reported.
Not reported.
Secondary outcomes
Secondary outcomes Change in isolated movement, objective and subjective measures of
speech production, within one month post intervention
speech production, measured within one month post intervention Buspirone had no effect on total ICARS scores (n = 19). The speech
Cooper 2008 measured ICARS scores of 43 participants in the subscale was not reported separately as an outcome. We requested
high-dose (n = 22) and low-dose (n = 21) groups and found no data on speech performance from the study authors, but data were
difference in change between the two. The ICARS speech subscale not available.
demonstrated a 0.05 decrease in the low-dose group and a 0.02 Change in quality of life scores related to communication within one
decrease in the high-dose group. Syllable repetitions decreased by month post intervention
0.6 in the low-dose group and 0.1 in the high-dose group. Time
taken (s) to read a standard passage increased in the low-dose Not reported.
group by 0.7 and by 3.0 s in the high-dose group. The rate of change
of the ICARS speech subscale was reported but not significantly intervention
different between groups. Post hoc analysis compared the two
groups on high and low doses with cross-sectional data from 77 Not reported.
untreated people with Friedreich ataxia. Participants were divided
Adverse effects
into four groups based on the size of GAA1 repeat length. Post hoc
analysis found that 10 participants in the low-dose group (n = 21) Minor adverse events included dizziness (one participant on
and 11 participants in the high-dose group (n = 22) had changes placebo, four on buspirone) and drowsiness (one participant on
in ICARS scores over two years, which were below the 95% CIs placebo, three on treatment). No serious adverse events occurred.
of the cross-sectional data. Sixteen of these participants had an
absolute improvement in ICARS score. Speech was also measured Burdens
by the time taken to read a standard passage and the repetitions Not reported.
of the syllables /pa/ and /ta/. None of these measures signified a
statistically significant improvement for low-dose versus high-dose Economic outcomes
groups.
Not reported.
month post intervention α-tocopheryl quinone versus placebo
Not reported. Lynch 2012 compared two doses of the antioxidant α-tocopheryl
quinone with placebo, in 31 participants with Friedreich ataxia. See
Generic quality of life measures a minimum of one month post Characteristics of included studies and Summary of findings 10.
intervention
Not reported. speech production immediately following completion of the
Adverse effects intervention or later, measured by any validated speech
assessment tool
No serious adverse events occurred among the 50 participants who
started the trial. Minor adverse events included one participant Not reported.
Informed decisions.
Secondary outcomes Generic quality of life measures a minimum of one month post
intervention
speech production, measured within one month post intervention Quality of life was measured with the SF-36. No difference was
observed between the rhuEPO and placebo groups (n = 16, P value
Speech was measured using a subscale of the FARS within the
= 0.18).
bulbar section of the exam. Data on speech outcomes within the
FARS were requested from the authors but not available. Adverse effects
Change in quality of life scores related to communication within one No serious adverse events occurred. Three female participants
month post intervention demonstrated sideropenic anaemia (two in the rhuEPO group and
Not reported. one in the placebo group). All participants underwent iron therapy.
Burdens
intervention Not reported.
The SF-36 (scored out of 100, higher is better) demonstrated an Economic outcomes
increase in self reported quality of life for the placebo group
(change of +3.26 (SD ± 5.0)) on day 28 compared to baseline, a Not reported.
decrease for the low-dose group (mean change of -4.77 (SD ± 5.7)
versus baseline) and a marginal decrease for the high-dose group DISCUSSION
(change of -0.01 (SD ± 5.31) versus baseline). These results were not
statistically significant. There are currently no studies describing an effective and clinically
significant treatment for speech disorder (dysarthria) in any
Adverse effects hereditary ataxia syndrome. Fourteen studies met the inclusion
criteria for the current review (Assadi 2007; Cooper 2008; Di
No severe drug-related adverse events occurred. Minor adverse Prospero 2007; Filla 1988; Lynch 2010; Lynch 2012; Mariotti 2009;
events occurred equally across the treatment arms. Miyai 2012; Ristori 2010; Sobue 1983; Trouillas 1995; Wessel
Burdens 1995; Zannolli 2012; Zesiewicz 2012). There were no studies
employing behavioural or instrumental interventions designed
Not reported. specifically to improve speech. One double-blind, placebo-
controlled, randomised study of the drug riluzole demonstrated
Economic outcomes
slight improvements in overall dysarthria in a cohort of 40
Not reported. individuals with cerebellar ataxia of mixed aetiologies (Ristori
2010). The investigators utilised a subjective assessment of
Erythropoietin (rhuEPO) versus placebo speech to measure change and included sporadic ataxia and
Mariotti 2009 compared rhuEPO and placebo in a group of ataxia of unknown origin alongside hereditary ataxias. A second
16 individuals with genetically confirmed Friedreich ataxia, in study, Zannolli 2012, demonstrated slight improvements in
a randomised, placebo-controlled, double-blind, dose-response dysarthria rating with betamethasone (BETA), in a cohort of 13
pilot trial. See Characteristics of included studies and Summary of individuals with ataxia telangiectasia using a subjective measure of
findings 11. speech. Di Prospero 2007 identified improvements in International
Cooperative Ataxia Rating Scale (ICARS) score in a study of
Primary outcome: Percentage change (improvement) in overall 48 people with Friedreich ataxia taking idebenone; however,
speech production immediately following completion of the improvements were small and a larger idebenone study involving
intervention or later, measured by any validated speech 70 people with Friedreich ataxia by Lynch 2010 did not find
assessment tool any improvement, despite mirroring the dose and length of the
Di Prospero 2007 study. Sobue 1983 identified slight, but not
Not reported. clinically meaningful, improvements on a subjective measure of
speech performance in a thyrotropin-releasing hormone (TRH)
Secondary outcomes
tartrate trial of 290 participants with spinocerebellar degeneration.
Change in isolated movement, objective and subjective measures of Conflicting findings were reported by Filla 1988, who did not find
speech production within one month post intervention a significant effect with the same drug in a study of 16 Friedreich
Speech was measured as part of the SARA. The speech subscale ataxia and spinocerebellar ataxia (SCA) participants. Assadi 2007,
scores were not reported separately. No difference was found on Cooper 2008, Mariotti 2009, Trouillas 1995, Wessel 1995 and
the SARA between rhuEPO and placebo groups (P value = 0.60, Zesiewicz 2012 did not find statistically significant differences
n = 16). The CI could not be calculated for Mariotti 2009, as no between intervention and placebo in each of their pharmaceutical
measure of the variance of change was reported. We requested trials. Miyai 2012 employed a combination of physiotherapy
data on speech performance from the study authors, but none were and occupational therapy within an inpatient setting. Short-term
available. improvements in 'functional independence' were documented in
the intervention group (compared to the no intervention group) but
Change in quality of life scores related to communication within one treatment effects were not present 12 weeks post intervention.
month post intervention
Assadi 2007, Wessel 1995, Zannolli 2012 and Filla 1988 utilised
Not reported.
a double-blind, cross-over, placebo-controlled methodology. Di
Informed decisions.
Prospero 2007, Lynch 2010, Lynch 2012, Mariotti 2009, Ristori number of psychometric limitations including poor intra- or inter-
2010, Sobue 1983, Trouillas 1995 and Zesiewicz 2012 were double- rater reliability, floor and ceiling effects, and the use of discrete
blind but not cross-over studies and Miyai 2012 was single- rather than continuous variables (Vogel 2010; Vogel 2011; Vogel
blinded. Cooper 2008 utilised a double-blind randomised design 2014). This means that the quality of the current evidence base for
with a low-dose group as placebo. The trials aimed to determine treatment of speech disorder in hereditary ataxia is no better than
whether treatment with pharmacotherapy (L-5HT in Wessel 1995 low.
and Trouillas 1995; TRH-T in Filla 1988 and Sobue 1983; varenicline
in Zesiewicz 2012; riluzole in Ristori 2010; idebenone in Di Prospero Potential biases in the review process
2007 and Lynch 2010; betamethasone in Zannolli 2012; CoQ10
This review only utilised published data available through searches
with vitamin E in Cooper 2008; buspirone in Assadi 2007; a- of electronic databases. We contacted the authors of five
tocopheryl quinone in Lynch 2012; and rhuEPO in Mariotti 2009) or methodologically appropriate randomised controlled trials (RCTs)
physiotherapy (Miyai 2012) could improve the conditions of people (Di Prospero 2007; Filla 1988; Lynch 2010; Lynch 2012; Ristori 2010),
with degenerative cerebellar ataxia. Only three of these studies with the aim of acquiring unpublished speech data; however, no
employed an objective motor speech outcome measure (repetition further data were available. This limited the information available
rates for syllables or timing of standard passages) (Cooper 2008; to us, as additional data might have provided new insights into the
Trouillas 1995; Wessel 1995). The remaining studies evaluated outcomes of the treatments. The Filla 1988 trial authors provided a
speech performance via subjective clinician-derived measures translation from the original Italian into English.
of severity as a component of an ataxia disease rating scales.
Subjective speech assessments lack adequate levels of intra- Agreements and disagreements with other studies or
and inter-rater reliability and are generally not psychometrically reviews
appropriate for monitoring change (Vogel 2010; Vogel 2011; Vogel
2014). One other systematic review has been published on treatments for
Friedreich ataxia; however, it did not deal with speech production
Summary of main results but rather overall clinical functioning. Kearney 2012 evaluated the
evidence for antioxidants and other pharmaceutical treatments
Given the paucity of empirical data on treatment for speech for Friedreich ataxia and concluded that no RCT using idebenone
disorder in Friedreich ataxia and other hereditary ataxia or any other pharmacological treatment has shown significant
syndromes, it was not possible to determine whether any benefit for the treatment of neurological symptoms associated with
treatment is clearly effective or if one type of treatment is Friedreich ataxia.
more effective than another for improving speech production.
No behavioural or instrumental treatment studies specifically AUTHORS' CONCLUSIONS
targeting speech were found within the search results.
Implications for practice
Overall completeness and applicability of evidence
The absence of treatment trials, let alone randomised controlled
There is no evidence of an effective treatment for speech disorder trials (RCTs), of effective therapies that improve speech production
in any hereditary ataxia syndrome. The majority of included trials in hereditary ataxia demonstrates the critical and urgent need for
employed subjective assessments of speech production and no more research in this area. There is at present no high quality
studies formally considered overall intelligibility or alternative evidence on which to base practice.
metrics of performance (for example, standardised assessment
tools). To date, the available evidence for treatment of speech Implications for research
disorder in hereditary ataxia is incomplete and not applicable in a
clinical setting. This review highlights the paucity of evidence for treatments of
speech disorder in hereditary ataxias. The reasons for the clear
Quality of the evidence lack of evidence are unknown; however, several factors may be
responsible:
The very high attrition rate within the Friedreich ataxia subgroup
in Wessel 1995 limits the interpretability of these data. The study • Speech deficits in neurodegenerative diseases are often
was also at high risk of bias due to the selective reporting of considered secondary to other more life-threatening
participant performance on a limited outcome regime. Sobue 1983 comorbidities (for example, cardiomyopathy) or adjunct signs
is at a high risk of attrition bias as speech outcomes for several affecting mobility, and do not therefore receive priority within
participants were not reported, with no explanation. Trouillas 1995, patient care plans.
Wessel 1995 and Zesiewicz 2012 are also at risk of attrition bias. • Speech clinicians often employ non-standardised treatment
Only three studies, Cooper 2008, Trouillas 1995 and Wessel 1995, regimes tailored to individual needs in response to areas of
employed an objective motor speech outcome measure. The use deficit, making wider comparisons difficult.
of a subjective speech assessment conducted by potentially poorly
• The three studies that included an objective measure of speech
blinded examiners limits the accuracy of data in Assadi 2007, Lynch
production (Cooper 2008; Trouillas 1995; Wessel 1995), did not
2012, Mariotti 2009, Miyai 2012 and Zannolli 2012. Speech outcomes
include broader and potentially more meaningful assessments
within several studies were further confounded as researchers used
looking at intelligibility or overall speech production. The
subjective measures of speech, which were not reported separately
remaining 11 studies employed subjective clinician-derived
to the total clinical severity rating (Assadi 2007; Di Prospero 2007;
measures of severity, which typically lack reliability and
Filla 1988; Lynch 2010; Mariotti 2009; Miyai 2012; Zesiewicz 2012).
sensitivity to change (Vogel 2011). In order for accurate
Perceptual (subjective) evaluation of speech is restricted by a
decisions to be made about the effectiveness of any treatment,
Informed decisions.
assessment models need to be tailored to monitoring change, • Another methodological difficulty that can arise in clinical
rather than identifying impairment. As stated, the speech populations relates to the willingness of participants to be
assessment tools used in 11 of the 14 included studies used randomly allocated into either a treatment group or non-
measures that were designed and well-suited for classification intervention control group.
or for identification of impairment. However, evidence from • Mobility is often a significant barrier to participation. Individuals
the clinical trials literature in related cognitive domains who rely on caregivers for transport may have limited capacity
has shown that a different practical, methodological and to participate in a treatment trial, which may be run intensively
statistical framework needs to be adopted in the assessment over consecutive weeks (for example, Lee Silverman Voice
of behaviour to guide decisions about change (Collie 2003). Treatment (Ramig 2001)).
Similar evidence in the speech literature has demonstrated • The rare nature of many hereditary ataxias, combined with
the need for stable, reliable and sensitive assessment the varied diagnostic types and severity of the disease, makes
protocols in trials where speech is changing as a function it difficult to recruit large numbers of sufficiently similar
of disease progression in Friedreich ataxia (Rosen 2012), participants to take part in trials.
Huntington's disease (Vogel 2012), treatment for depression
(Mundt 2012), or induced neurophysiological change resulting For these barriers to be overcome, large, potentially multinational,
from sustained wakefulness (Vogel 2010b). Briefly, assessments multicentre randomised clinical trials need to be established to
examining change need to be sensitive to impairment, while determine the effectiveness of specific treatment options.
simultaneously remaining stable in the absence of true change.
Tasks should be designed to limit the impact of practice and ACKNOWLEDGEMENTS
familiarity by remaining brief, easy to complete and suitably
motivating. They should preferably have alternate forms, and We wish to thank the members of the Cochrane Neuromuscular
be partnered with appropriate statistical models. Similarly, Disease Review Group for their assistance and acknowledge the
assessments that fail to satisfy assumptions of normality or do patients of the Friedreich Ataxia Clinic, Monash Medical Centre,
not utilise continuous variables may produce data with floor or Melbourne, Australia.
ceiling effects, again limiting their sensitivity to change (Vogel
2014). In light of these considerations, the use of subjective The editorial base of the Neuromuscular Disease Group receives
evaluation tools in the included studies may mean that the true support from the MRC Centre for Neuromuscular Diseases.
impact of the tested therapies is unknown.
Informed decisions.
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Trouillas P, Xie J, Adeleine P, Michel D, Vighetto A, Honnorat J, Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an
et al. Buspirone, a 5-hydroxytryptamine1A agonist, is active overview. Journal of Medical Genetics 2000;37(1):1-8.
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2011;10(1):1-8. [DOI: 10.1007/s12311-010-0212-7] et al. Clinical and genetic abnormalities in patients with
Friedreich's ataxia. New England Journal of Medicine
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(Clinical Neurology) 1999;39(8):793-9. Filla A, Sacca F, De Michele G. A randomized trial of varenicline
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Schöls L, Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C.
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molecular genetics. Brain 1997;120(Pt 12):2131-40. * Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Assadi 2007
Methods Randomised, double-blind, placebo-controlled, cross-over trial
Participants 20 individuals with SCA or Friedreich ataxia were recruited and 19 completed the protocol. Of these,
14 were genetically confirmed (4 Friedreich ataxia, 1 SCA1, 4 SCA2, 2 SCA3, 1 SCA6, 1 SCA17, 1 denta-
torubral-pallidoluysian atrophy (DRPLA)) and 6 were idiopathic. Participants had clinically sympto-
matic ataxia and either cerebellar or brainstem atrophy on imaging studies or genetic confirmation of a
hereditary SCA
Interventions Participants received either buspirone hydrochloride 30 mg twice daily or placebo for 12 weeks. A titra-
tion period was implemented in the 1st 2 weeks of each arm (10 mg buspirone twice daily in week 1; 20
mg buspirone twice daily in week 2). A 4-week washout period followed the 1st treatment phase, after
which participants were crossed into the alternative treatment arm
Informed decisions.
Assadi 2007 (Continued)
Outcomes ICARS, which includes an 8-point speech subscale, was used to evaluate clinical features at baseline
and at the end of each treatment phase (12 weeks' duration). The speech subscale was not reported
separately to the total ICARS score
Notes Several participants (6/20) were diagnosed with an idiopathic type of cerebellar degeneration (without
a confirmed genetic diagnosis)
Mr and Mrs Dennis Culnan provided the funding for the study. The provider of buspirone and placebo is
not stated
Risk of bias
Bias Authors' judgement Support for judgement
Random sequence genera- Unclear risk Method of randomisation is not clear

tion (selection bias)
Allocation concealment Unclear risk Method of allocation concealment is not clear

(selection bias)
Blinding of participants Unclear risk Blinding of participants and personnel is not clear
and personnel (perfor-
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Blinding of investigators at assessment is not clear
sessment (detection bias)
All outcomes
Selective reporting (re- Low risk All planned outcomes are reported
porting bias)
Incomplete outcome data Low risk 1 participant withdrew from the protocol after moving away from the treat-
(attrition bias) ment site
All outcomes
Other bias Low risk None identified
Cooper 2008
Methods Double-blind randomised trial with high-dose and low-dose groups
Participants 50 participants with a diagnosis of Friedreich ataxia (genetically confirmed)
Interventions Participants were split into high-dose and low-dose groups. The high-dose group received 2100 IU/day
vitamin E and 600 mg/day coenzyme Q10 (CoQ10) (participants under 18 years of age received 30 IU/kg/
day vitamin E and 9 mg/kg/day CoQ10). The low-dose group received 30 mg CoQ10 and placebo tablets
containing 4 IU/day of vitamin E, which were indistinguishable from active vitamin E tablets. Partici-
pants received treatment over a 2-year study period
Outcomes Primary outcome measure: ICARS (including an 8-point speech subscale)
Further outcome measures included ICARS subscales (including speech), speech tests (passage test,
PaTa test), limb co-ordination, heart function and an ADL questionnaire. Testing occurred at baseline
and every 6 months for 2 years
Informed decisions.
Cooper 2008 (Continued)
Notes Pharma Nord, Morpeth, UK provided vitamin E and CoQ10. The study was supported by grants from
Ataxia UK, the Wellcome Trust and the Medical Research Council
Risk of bias
Random sequence genera- Low risk A statistician external to the study randomised participants to give 2 groups of
tion (selection bias) 24 and 26 participants matched for age, GAA1 repeat size, cardiac hypertrophy
and clinical severity (ICARS)
Allocation concealment Low risk The researchers were not involved in the allocation sequence, which was de-
(selection bias) vised by an external statistician
Blinding of participants Low risk The treatment was independently dispensed by the hospital pharmacy
mance bias)
All outcomes
Blinding of outcome as- Low risk Assessors were blind to the treatment received by participants
All outcomes
Selective reporting (re- Low risk All outcomes reported either in the article or in supplementary online tables
porting bias)
Incomplete outcome data Low risk 22/26 participants completed the high-dose treatment
(attrition bias)
All outcomes 21/24 participants completed the low-dose treatment
Other bias Unclear risk Results of the randomised controlled (low-dose group) segment of the study
were not significant. Post hoc analysis was completed using a cross-sectional
data set of untreated participants, which is not adequately described
Di Prospero 2007
Methods Randomised, double-blind, placebo-controlled study with 3 treatment groups and 1 control group
Participants 48 participants with Friedreich ataxia (genetically confirmed) aged 9 to 17 years of age and weighing 30
kg to 80 kg
47 participants (24 male, 23 female) were assessed post treatment with a mean age of 13.4 years (SD
2.4). A subgroup excluding non-symptomatic and non-ambulatory participants involved 33 partici-
pants (16 male, 17 female) with a mean age of 12.8 years (SD 2.3)
Participants were not exposed to idebenone, coenzyme Q10 or other dietary supplements for a period
of 1 month prior to enrolment
Interventions Participants took either a low dose, intermediate dose or high dose of idebenone over a period of 6
months. Doses were stratified according to weight (≤ 45 kg or > 45 kg): low dose (180 mg or 360 mg), in-
termediate dose (450 mg or 900 mg) and high dose (1350 mg or 2250 mg). The total daily dose was di-
vided and taken 3 times each day
Outcomes Participants were scored on ICARS, which contains a subjective dysarthria rating scale and FARS,
which includes a rating of speech within a neurological examination subscore. An ADL survey devel-
Informed decisions.
Di Prospero 2007 (Continued)

oped alongside the FARS was also completed. Scores were obtained at baseline and after 6 months'
idebenone or placebo, by a single rater
Notes Idebenone and placebo were provided by Santhera Pharmaceuticals (Liestal, Switzerland). The study
was supported by intramural NIH research funds
Risk of bias
Random sequence genera- Low risk Computer-generated random allocation, stratified by body weight (to main-
tion (selection bias) tain dose range) and the shorter GAA repeat length (to control for disease pro-
gression)
Allocation concealment Low risk The list of randomised numbers and corresponding treatment numbers was
(selection bias) computer-generated by a third party (Hesperion Ltd, Allschwil, Switzerland).
Participants and investigators were blind to the allocated study treatment.
The allocations were maintained by the 3rd party and only made available
when the trial was complete
Blinding of participants Low risk Participants were blinded to their treatment allocation. The manufacturer pro-
and personnel (perfor- vided idebenone or placebo in prepackaged kits marked with treatment num-
mance bias) bers
All outcomes
Blinding of outcome as- Low risk Investigators were blinded to the treatment groups
All outcomes
Selective reporting (re- Unclear risk All outcomes were reported. The second statistical analysis, which was con-
porting bias) ducted to remove potential ceiling and floor effects, involved seemingly ar-
bitrary cut-off points (including baseline scores between 10 and 54 on a 100-
point scale). The process effectively removed non-ambulatory participants
and 1 participant with no symptoms
Incomplete outcome data Unclear risk One participant from the low-dose idebenone group did not complete the fol-
(attrition bias) low-up assessment due to "intercurrent illness"
All outcomes
Filla 1988
Methods Double-blind, placebo-controlled, cross-over study using an ABCB design
Participants 17 participants with Friedreich ataxia (not genetically confirmed) (8 female, 9 male, mean age 23.4
years (± 8.1 years)) and 14 participants with other SCAs (6 female, 8 male, mean age 47.1 years (± 13.4
years)) including: 10 with autosomal dominant cerebellar ataxia, 2 with idiopathic late onset cerebellar
ataxia (not genetically confirmed), 1 with autosomal recessive late onset cerebellar ataxia (no formal
diagnosis) and 1 with early onset cerebellar ataxia with retained tendon reflexes (not genetically con-
firmed)
Interventions Thyrotropin-releasing hormone tartrate (TRH-T) or placebo were administered intramuscularly. There
were 2 sequences (groups of participants) within the study: sequence I began the study in the placebo
arm, sequence II in the active treatment arm (TRH-T). 9 participants with Friedreich ataxia and 6 partic-
ipants with SCA underwent sequence I (1st month with placebo). 7 participants with Friedreich ataxia
and 9 participants with SCA underwent sequence II (1st month with TRH 2 mg). Each treatment was ad-
Informed decisions.
Filla 1988 (Continued)

ministered for 1 month in a double cross-over design. Participants were allocated randomly to either
sequence. The daily dose of TRH-T was 2 mg for the 1st month and 4 mg for the 2nd active treatment
phase
Outcomes Neurological and clinical function were evaluated using the Inherited Ataxias Clinical Rating Scale
(IACRS) which contains a speech component. The study neurologist, blinded to the treatment condi-
tion, evaluated speech subjectively using a categorical scale where 0 reflected 'normal' function and 4
was considered 'not understandable'
Notes 6 participants remained on their pre-existing pharmaceutical treatment regime throughout the experi-
ment. Diagnosis was not genetically confirmed for the cohort as the genes for the respective disorders
had not yet been identified (Campuzano 1996; Orr 1993)
Cyanamid Italia, Italy provided TRH-T and matching placebo
Risk of bias
Random sequence genera- Unclear risk Participants were randomly allocated to TRH-T or placebo. Given the rela-
tion (selection bias) tively even distribution of participants with Friedreich ataxia and SCA in the 2
groups, the random nature of the selection is unclear
Allocation concealment Unclear risk Not stated

(selection bias)
Blinding of participants Low risk Participants blinded to treatment condition

mance bias)
All outcomes
Blinding of outcome as- Low risk Assessor blinded to treatment condition. The same experimenter conducted
sessment (detection bias) the assessments over the course of the trial
All outcomes
Selective reporting (re- Low risk All planned outcomes reported

porting bias)
Incomplete outcome data Unclear risk 1 participant in the Friedreich ataxia group dropped out
(attrition bias)
All outcomes
Other bias Unclear risk Dose strength was not randomised (2 mg in the 1st treatment phase and 4 mg
in the 2nd)
Lynch 2010
Methods Randomised, double-blind, placebo-controlled trial with 3 treatment arms: low-dose idebenone, high-
dose idebenone and placebo
Participants 70 ambulatory children (33 male, 37 female) aged 8 to 18 years (mean age 13.7 years, SD 2.8) with
Friedreich ataxia (with confirmed GAA expansion mutations). Children with an ICARS scores less than
10 or greater than 54 were excluded
Interventions 3 treatment arms received either idebenone or placebo for 24 weeks. Group A received a low dose of
either 450 mg/day (body weight ≤ 45 kg) or 900 mg/day (body weight > 45 kg). Group B received a high
Informed decisions.
Lynch 2010 (Continued)

dose of either 1350 mg/day (body weight ≤ 45 kg) or 2250 mg/day (body weight > 45 kg). Group C re-
ceived placebo. Daily dosages were divided into 3 tablets per day
Outcomes Outcomes were measured at baseline, 12 weeks and 24 weeks after the beginning of treatment. Partici-
pants were scored on the ICARS, which contains a speech subscale, and the FARS, which includes a sub-
jective rating of speech within a neurological examination subscore
Notes Santhera Pharmaceuticals (Liestal, Switzerland) provided idebenone and funding
Risk of bias
Random sequence genera- Low risk Allocation to treatment arms was computer-generated
Allocation concealment Low risk A third party (Fischer Services, Allschwil, Switzerland) conducted random allo-
(selection bias) cation to treatment arms
Blinding of participants Low risk Participants were blinded to their allocation and received prepackaged kits of
and personnel (perfor- either placebo or idebenone marked with their treatment number
mance bias)
All outcomes
Blinding of outcome as- Low risk Treatment assignments were maintained by the third party and not revealed
sessment (detection bias) to investigators until the trial was completed
All outcomes
Selective reporting (re- Low risk All planned outcomes were reported
porting bias)
Incomplete outcome data Low risk All participants who were allocated to study arms completed all assessments
(attrition bias)
All outcomes
Lynch 2012
Methods Double-blind, placebo-controlled, randomised trial involving 3 treatment arms (placebo, low-dose α-
tocopheryl quinone (510 mg/day) or high-dose α-tocopheryl quinone (EPI-A0001) (750 mg/day))
Participants 31 participants with genetically confirmed Friedreich ataxia aged between 18 and 60 years. 10 partici-
pants were randomised into the placebo arm, 11 into the low-dose α-tocopheryl quinone arm and 10
into the high-dose α-tocopheryl quinone arm
Interventions Participants received capsules containing either 250 mg or 170 mg of α-tocopheryl quinone in olive
oil 3 times daily with meals. The placebo group received identical capsules containing 0.01% be-
ta-carotene in olive oil. Treatment was provided for 28 days
Outcomes Outcomes were measured at baseline, at 14 days of treatment and at 28 days of treatment. The primary
study outcome was a measure of diabetic tendency. Secondary outcome measures included the FARS
and SF-36
Notes The Friedreich Ataxia Research Alliance and Penwest Pharmaceutical provided funding
Informed decisions.
Lynch 2012 (Continued)

Authors Lynch and Willi received grant support from Penwest Pharmaceutical to undertake the study.
Authors Hawi and Sciascia were employed by Penwest during the study. Authors Miller and Shrader
held stock in Edison Pharmaceuticals (owner of EPI-A0001). Author Miller was an employee and re-
ceived 100% of his compensation from Edison Pharmaceuticals. Author Shrader was a compensated
consultant for Edison Pharmaceuticals. Author Rioux had been previously employed by Edison Phar-
maceuticals. Provider of the drug for this study is not stated
Risk of bias
Random sequence genera- High risk The method of randomisation is not clear and did not completely match the 3
tion (selection bias) groups. The placebo group had higher clinical severity scores
Allocation concealment Unclear risk The method of allocation concealment is not clear
(selection bias)
Blinding of participants Low risk Participants were blinded to the treatment by the use of identical capsules for
and personnel (perfor- α-tocopheryl quinone and placebo
mance bias)
All outcomes
Blinding of outcome as- Unclear risk It is not clear how examiners were blinded to the treatments
All outcomes
Selective reporting (re- Low risk All planned outcomes were reported
porting bias)
Incomplete outcome data Low risk One participant from the high-dose α-tocopheryl quinone arm discontinued
(attrition bias) treatment due to a major protocol violation
All outcomes
Mariotti 2009
Methods Randomised, placebo-controlled, double-blind, dose-response pilot trial
Participants 16 participants (9 female, 7 male) with genetically confirmed Friedreich ataxia, aged 18 to 40 years. 11
received recombinant human erythropoietin (rhuEPO) and 5 received placebo
Interventions Participants received either rhuEPO or placebo over a period of 24 weeks. Dosage was 20,000 IU every 3
weeks for 9 weeks (visits 1 to 3), 40,000 IU every 3 weeks for 9 weeks (visits 4 to 6) and 40,000 IU every 2
weeks for 6 weeks (visits 7 to 9)
Outcomes Primary outcome measures were of safety and tolerability of rhuEPO and efficacy of rhuEPO in increas-
ing frataxin in peripheral lymphocytes. Secondary outcome measures included the SARA and SF-36
Notes The study was funded by the Italian Agency for Pharmaceutics (Agenzia Italiana del Farmaco; AIFA
grant FARM6H95MJ; to F.T.) EPREX, Janssen-Cilag, Cologno Monzese, Milan, Italy provided RhuEPO
Risk of bias
Informed decisions.
Mariotti 2009 (Continued)
Random sequence genera- Unclear risk Participants were randomly assigned to rhuEPO or placebo at a ratio of 2:1.
tion (selection bias) The method of randomisation is unclear given the similarity of the genetic and
clinical characteristics of the participants in each group
Allocation concealment Unclear risk Method of allocation concealment is not clear

(selection bias)
Blinding of participants Unclear risk Participants reportedly blinded to treatment conditions, however the method
and personnel (perfor- used is not described
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Assessor reportedly blinded to treatment conditions, however the method
sessment (detection bias) used is not described
All outcomes

porting bias)
Incomplete outcome data Low risk All enrolled participants completed the protocol
(attrition bias)
All outcomes
Miyai 2012
Methods Single-blinded randomised design with delayed intervention arm versus immediate intervention arm
Participants 20 participants with SCA type 6 (genetically confirmed), 6 participants with SCA31 (genetically con-
firmed) and 16 participants with ICA presenting with pure cerebellar ataxia (negative DNA result for
known SCAs)
Immediate treatment group: 8 SCA6, 2 SCA31 and 11 ICA participants; 8 female, 13 male; mean age 63.5
years (standard error (SE) 2.4 years), mean disease duration 9.3 years (SE 1.3 years)
Delayed treatment group: 12 SCA6, 4 SCA31 and 5 ICA, 12 female, 9 male, mean age 61.5 years (SE 2.3
years), mean disease duration 10.3 years (SE 1.4 years)
Interventions Inpatient hospital setting over the course of 4 weeks.
Immediate treatment group: 2 hours of physical therapy (focusing on posture and gait) and occupa-
tional therapy (focusing on ADL) on weekdays and 1 hour on weekends. Delayed treatment group (con-
trol): the same intervention after a 4-week delay
Outcomes Primary outcome measures were derived from changes in baseline end point scores (at completion of
intervention, and 4, 12 and 24 weeks post intervention) of the SARA. The SARA contains a subscale fo-
cusing on speech function. The study protocol also included a standardised scale of functional inde-
pendence, the Functional Independence Measure (FIM). Only data from the short-term component of
the trial (up to 4 weeks) was randomised, all subsequent time points were part of the follow-up obser-
vational study and not included in this review
Notes Description of the interventions and their relationship with the services provided in an inpatient hospi-
tal setting were not clearly described. A large proportion of participants (16/42) were diagnosed with an
idiopathic type of cerebellar degeneration (without a confirmed genetic diagnosis)
Informed decisions.
Miyai 2012 (Continued)

The study author(s) declared no potential conflicts of interest. Grants from various governmental agen-
cies declared as sources of support
Risk of bias
Random sequence genera- Low risk Participants were randomly allocated to immediate or delayed entry groups.
tion (selection bias) We believe this process was adhered to given the uneven (and potentially con-
founding) distribution of disease types in the 2 groups
Allocation concealment Low risk Sealed envelopes with allocation information on groups (immediate or de-
(selection bias) layed entry control group) were randomly selected by a person who was not
involved in this study
Blinding of participants High risk No sham or alternative treatment was included. Participants would have
and personnel (perfor- known they were being treated; however, they may have been blinded to the
mance bias) type of treatment
All outcomes
Blinding of outcome as- Unclear risk It is difficult to determine whether those assessing the study participants were
sessment (detection bias) in contact with the treating clinicians. Assessments were conducted by physi-
All outcomes cians or therapists familiar with the measures. They were reportedly blinded
to the group allocation but the additional effect of inpatient stay, in conjunc-
tion to the treatment regime, was not clearly described

porting bias)
Incomplete outcome data Low risk All randomised participants completed the trial. 1 participant died during the
(attrition bias) follow-up observational component of the study as a result of cerebral haem-
All outcomes orrhage at 17 weeks (outside the randomisation period)
Other bias High risk Participants were treated in an inpatient setting within a hospital and may
have been exposed to additional therapeutic care during their stay
Ristori 2010
Methods Double-blind, placebo-controlled, randomised study
Participants 40 participants (between 18 and 80 years) with chronic cerebellar ataxia (bilateral involvement of static
and kinetic functions, as well as dysarthria and oculomotor dysfunction), irrespective of aetiology
Riluzole group: 20 participants (8 male, 12 female), mean age 48.9 (SD 16.8)
Control group: 20 participants (7 male, 13 female), mean age 44.1 (SD 13.1)
The riluzole group included 10 participants with hereditary ataxia (6 SCA, 3 Friedreich ataxia, 1 fragile X
tremor/ataxia syndrome), 5 with sporadic ataxia (3 with probable multiple system atrophy type C (MSA-
C), 1 with anti-GAD antibodies, 1 with anti-Yo antibodies) and 5 with ataxic syndromes of unknown ori-
gin
The placebo group included 7 participants with hereditary ataxia (2 SCA, 5 Friedreich ataxia), 5 with
sporadic ataxia (3 with probable MSA-C, 2 with multiple sclerosis) and 8 with ataxic syndromes of un-
known origin
Informed decisions.
Ristori 2010 (Continued)
Interventions Participants received riluzole (50 mg tablets, twice daily) or placebo for a period of 8 weeks. Partici-
pants suspended any pharmacological or physical therapy for ataxia for 2 weeks prior to enrolment
Outcomes Participants were assessed at baseline, 4 weeks and 8 weeks after the beginning of treatment, for
symptoms, physical and neurological signs, ICARS score, electrocardiogram and complete standard
laboratory safety tests. Treatment efficacy was measured by differences between riluzole and placebo
groups in:
• the proportion of participants who showed a decrease of at least 5 points on the ICARS after 4 and
8 weeks
• mean changes of ICARS score from baseline to treatment (total score and subscores at 8 weeks) safety
and tolerability (number, type and severity of adverse events)
The ICARS assessment contains a dysarthria subscale which was only reported separately for the mean
change of ICARS scores from baseline to 8 weeks after beginning of treatment
Notes Only 17 out of 40 participants presented with symptoms caused by hereditary ataxia. Outcomes of the
dysarthria subscale only were not reported for either individual participants; or groups according to ae-
tiology or diagnosis
Sanofi-Aventis (Milan, Italy) provided riluzole and matching placebo
Risk of bias
Random sequence genera- Low risk Participants were randomly assigned in a 1:1 ratio to riluzole or placebo
tion (selection bias) groups. Given the relatively uneven distribution of participants with different
diagnoses in the 2 groups, the random nature of the allocation appears clear
Allocation concealment Low risk A list of randomisation numbers and corresponding treatment numbers was
(selection bias) computer-generated before the start of the study. This procedure was central-
ly performed by personnel not involved in the study measurements
Blinding of participants Low risk Both examiner and participant were blinded to treatment
mance bias)
All outcomes
Blinding of outcome as- Low risk A treating investigator assessed the safety of riluzole and took all the medical
sessment (detection bias) decisions on the basis of the clinical and laboratory findings. A second exam-
All outcomes ining investigator had access to the ICARS score but was unaware of the treat-
ment groups until all the data had been collected and analysed (data were
first entered into a paper case report form, then into electronic databases for
analysis). This prevented the blinding procedure from being broken as a result
of observed efficacy, adverse events or changes in laboratory tests

porting bias)
Incomplete outcome data Low risk 2 participants (1 in the riluzole and the other in the placebo arm) withdrew
(attrition bias) their consent before receiving riluzole or placebo and were excluded from the
All outcomes final analysis
Informed decisions.
Sobue 1983
Methods Randomised, double-blind, placebo-controlled study
Participants 290 participants with SCD. Participants were all hospital inpatients with an age range of 15 to 79 years.
Of the 290 people originally recruited, 256 met criteria for evaluation of efficacy. Of these, 220 were di-
agnosed with a predominantly cerebellar form of SCD (i.e. parenchymatous cerebellar degeneration,
including 80 participants with late onset cerebellar cortical atrophy (LCCA) and 140 participants with
olivopontocerebellar atrophy (OPCA)), 19 were diagnosed with cerebellospinal form of SCD and 17 had
a diagnosis which was unclassified. Of these with a predominantly cerebellar form of SCD, 214 com-
pleted all speech assessments
Interventions Participants received intramuscular thyrotropin-releasing hormone tartrate (TRH-T) or placebo. Partic-
ipants were randomised into 1 of 3 arms: 2 mg of TRH-T, 0.5 mg of TRH-T or placebo (5% sorbitol solu-
tion). Each arm received these doses once a day for 2 weeks. Participants were not permitted to contin-
ue with concomitant medications which may have affected ataxic symptoms, however 'routine rehabil-
itation' was allowed to continue
Outcomes Participants were assessed 4 times: at baseline, 1 week after commencing treatment, at the end of
treatment (2 weeks) and 1 week after completing the treatment. Participants underwent a neurological
examination and subjective rating of ataxic symptoms, with each symptom rated on a 14-point VAS. At
the end of the trial, the investigating physician made a 'global improvement rating' and an 'ataxia im-
provement rating', each of which involved a 7-point scale from 'markedly improved' to 'markedly ag-
gravated'. Speech was rated on the 'speed precision and rhythm of tongue-twisters' on a 14-point VAS.
Participants completed a self rating of the impact of ataxic symptoms on ADL, including a subscale for
speech
Notes This work was supported by a grant for the new drug development of the Ministry of Health and Welfare
of Japan. Takeda Chemical Industries, Ltd., Osaka, Japan provided TRH-T
Risk of bias
Random sequence genera- Unclear risk The method of randomisation was not described. Distribution of demograph-
tion (selection bias) ics and diagnostic characteristics (age, sex, duration of illness, hereditary fac-
tors) were reportedly similar in the 3 treatment arms
Allocation concealment Unclear risk The method of allocation is not described

(selection bias)
Blinding of participants Low risk Participants were blinded to treatment allocation

mance bias)
All outcomes
Blinding of outcome as- High risk Investigators were reportedly blinded to the treatment provided; however, it
sessment (detection bias) is not clear if clinicians rating the efficacy were also assessing safety and there-
All outcomes fore aware of adverse effects of treatment, which would have undermined
blinding
Selective reporting (re- High risk Results of the 'global improvement rating' were reported for the 3 groups
porting bias) stratified by diagnosis (predominantly cerebellar SCD, cerebellospinal SCD or
unclassified); however, the 'ataxia improvement rating', 14-point VAS for each
ataxic symptom and participant-rated ADL were only reported for the predom-
inantly cerebellar SCD group
Mean scores of the 14-point scales were not reported. Instead an improve-
ment ratio demonstrated the rate of responses which had improved by either
1 point on the 14-point scale or 2 points on the 14-point scale. This creates dif-
Informed decisions.
Sobue 1983 (Continued)

ficulty in interpreting the overall clinical significance of any statistically signifi-
cant results
Incomplete outcome data High risk Only 254 participants satisfied criteria for inclusion in the efficacy trial. 2 more
(attrition bias) participants were excluded from the trial as they had begun rehabilitation at
All outcomes the same time as the trial. VAS results of specific symptoms (e.g. dysarthria)
were only reported for 218 participants with a predominantly cerebellar form
of SCD, as this was the only diagnostic group to demonstrate statistically sig-
nificant differences on the 'global improvement rating'. The results of the in-
vestigator-rated dysarthria scale were reported for 216 participants at the 1-
week time point, 214 participants at 2 weeks and 214 participants at 3 weeks.
Participant-rated dysarthria was reported for 212 participants at 1 week, 210
participants at 2 weeks and 210 participants at 3 weeks. No explanation is pro-
vided by the authors for these latter reductions in participant numbers
Trouillas 1995
Methods Randomised, double-blind, placebo-controlled trial
Participants 26 participants with Friedreich ataxia (diagnosed by clinical symptoms) were recruited from 12 centres
in France. Only 19 participants (mean age 25.9 years, SD 8.1) from 8 centres completed the study. 11
participants with a mean age of 28.5 years (SD 9.4) received the levorotatory form of 5-hydroxytrypto-
phan (L-5HT) and 8 participants with a mean age of 22.3 years (SD 4.1) received placebo
Interventions Participants received L-5HT or placebo for 6 months. Dose was progressively increased in the treat-
ment arm based on participant weight as follows: weight < 50 kg, 200 mg/day for the 1st month, 600
mg/day for the remaining 5 months; weight > 50 kg, 300 mg/day for the 1st month, then 900 mg/day for
the remaining 5 months
Participants in the control arm received gelules of the same size and number as their counterparts in
the treatment arm
Outcomes Post treatment assessments versus baseline were made every 2 months for 6 months
Clinical symptoms were evaluated with a modified ataxia rating scale involving kinetic and static tasks,
which did not include speech tasks. Quantitative values were obtained including: mean time for writ-
ing a standard sentence, mean time for pronouncing a standard sentence. 3 tests measured the time of
standing in a natural position
Notes Dose was not consistent for all participants randomised in the treatment arm
The provider of L-5HT is not stated. Panmedica Laboratories, Carros, France funded the study
Risk of bias
Random sequence genera- Unclear risk The method of random allocation is not described
Allocation concealment Unclear risk The method of allocation concealment is not described
(selection bias)
Informed decisions.
Trouillas 1995 (Continued)
Blinding of participants Low risk Participants in the control arm received gelules of same size and number as
and personnel (perfor- the treatment group
mance bias)
All outcomes
Blinding of outcome as- High risk The method of blinding of investigators is not outlined. Experience of adverse
sessment (detection bias) effects in the treatment arm may have weakened the blinding process
All outcomes

porting bias)
Incomplete outcome data High risk Only 19/26 participants completed the study. 4 did not complete from the
(attrition bias) placebo group (due to "secondary refusal of consent", "no respect of regi-
All outcomes men", "cardiac flutter" and "general discomfort") and 3 from the treatment
group (2 due to "vomiting and gastralgia" and 1 to "no respect of regimen")
Wessel 1995
Methods Double-blind, placebo-controlled, cross-over study
Participants 19 participants with Friedreich ataxia, 13 with cerebellar atrophy and 7 with olivopontocerebellar at-
rophy. Age and sex of participants are not provided. Mean age of onset of symptoms for the Freidreich
ataxia participants was 20 years. Mean age of onset of the other conditions is not stated
Interventions Oral L-5HT 1000 mg/day or placebo. "Each treatment phase, with L-5HT or placebo, lasted 10 months,
after which the treatment of participants was crossed over to the other phase."
Outcomes "Ataxia was documented and quantified by using a clinical score, posturography, measurement of grip
force and the rapid-syllable repetition rate."
Notes Only 4 of the original 19 participants with Friedreich ataxia completed the speech assessments during
both arms of the experiment
Provider of L-5HT is not stated
Risk of bias
Random sequence genera- Unclear risk Participants were randomly allocated to either placebo or L-5HT. The distribu-
tion (selection bias) tion of participants within groups is not stated

(selection bias)
Blinding of participants High risk There is a possibility of unblinding due to adverse events. L-5HT in daily oral
and personnel (perfor- doses of 900 mg to 1000 mg commonly has gastrointestinal adverse effects
mance bias)
All outcomes
Blinding of outcome as- Low risk Multisite study utilising clinician-derived measures of severity which rely on
sessment (detection bias) clinician judgement. The assessor was blinded to the treatment condition
Informed decisions.
Wessel 1995 (Continued)

All outcomes
Selective reporting (re- High risk The primary outcome related to speech was only reported for a small group (4
porting bias) out of 19) of participants with Friedreich ataxia. It is unclear if other outcomes
were reported
Incomplete outcome data High risk Data for Friedreich ataxia participants were reported separately and showed
(attrition bias) that only a small group of randomised participants completed the study
All outcomes
Zannolli 2012
Methods Double-blind, randomised, placebo-controlled, cross-over study
Participants 13 participants (6 female, 7 male) with either a molecular diagnosis of ataxia telangiectasia based on
ATM gene mutations or an alpha-fetoprotein level more than twice the normal upper limit and an ATM
protein deficiency. All participants were ambulatory
Interventions Participants were provided with an oral course of BETA (betamethasone disodium phosphate drops (1
drop, 0.0125 mg)) or placebo in a 2-phase cross-over design. Each treatment phase lasted 30 days. Dur-
ing the 1st 10 and last 10 days, participants received the full dose of 0.1 mg/kg every 24 hours. During
the 10 days in the middle of the treatment phase, participants received a tapered dose of three-quar-
ters the daily dose for 4 days, half the daily dose for 4 days and a quarter the daily dose for 2 days. Each
phase was followed by a washout period of 30 days
Outcomes Primary outcome measure: the total ICARS score. Secondary outcomes included ICARS subscale scores,
a quality of life measure (Child Health Questionnaire), vital signs and biochemistry. Results are provid-
ed for both ITT and per protocol participants. Results of the ITT population are used for the purpose of
this review
ICARS outcomes were measured by calculating the difference between the changes in ICARS scores be-
tween BETA and placebo treatments
Notes The study was funded by the nonprofit organisation Fondazione Monte Paschi Siena (FMPS). The
provider of BETA is not stated
Risk of bias
Random sequence genera- Unclear risk The trial was centrally randomised in block sizes of 4. Group allocation is not
tion (selection bias) provided alongside participants' details

(selection bias)
Blinding of participants Low risk BETA and placebo were issued to participants in identical packaging
mance bias)
All outcomes
Blinding of outcome as- Unclear risk Unclear how the examiners were blinded to the treatment
All outcomes
Informed decisions.
Zannolli 2012 (Continued)

porting bias)
Incomplete outcome data Unclear risk 1 participant voluntarily discontinued treatment at the end of the 1st treat-
(attrition bias) ment phase, and a further 2 participants were excluded from the per proto-
All outcomes col analysis because their plasma levels of BETA were below the lower limit of
quantitation at each assessment. Results were provided for both ITT and per
protocol populations
Zesiewicz 2012
Methods Double-blind, placebo-controlled, randomised study
Participants 20 participants with a genetically confirmed diagnosis of SCA3 were recruited and 18 entered the first
phase. The mean age of participants in the varenicline group (5 female, 4 male (1 additional participant
omitted from analyses)) was 47.44 years (± 10.83 years). The mean disease duration was 14 years (± 9.82
years). The mean age of the placebo group (3 female, 7 male randomised) was 53.8 years (± 11.2 years)
Interventions Participants received oral varenicline (1 mg twice daily) or placebo. The treatment phase lasted 56 days
with a subsequent washout phase of 57 to 83 days for both placebo and varenicline. Participants were
allowed to continue taking all concomitant medications for the duration of the study
Outcomes Primary outcome measures were derived from changes in baseline to end point scores of the SARA. The
SARA contains a subscale focusing on speech function. The study protocol also included a standardised
scale of functional health and wellbeing, the SF-36
Notes No power calculations were made to determine the required number of participants to accurately de-
termine drug efficacy. Only 5 participants completed the placebo arm and 8 completed the varenicline
arm of the study. There was no correction for multiple comparisons due to small sample size. Clinical
presentation at baseline assessment was statistically significantly worse for the placebo group on the
'sitting' subscale in SARA
Varenicline and matching placebo were provided by Pfizer Inc., USA. The National Ataxia Foundation,
USA, and the Bobby Allison Ataxia Research Center (BAARC), USA provided funding
Risk of bias
Random sequence genera- High risk A 1:1 randomisation schedule was generated with Statistical Analysis Sys-
tion (selection bias) tem (SAS) 9.2 using a block size of 10. Participants were randomly allocated
to either placebo or varenicline; however, the small sample size and blocked
randomisation may have prevented equal distribution between groups. The
placebo group had higher clinical severity scores and appeared on average
older than the varenicline group, possibly influencing their responsiveness to
treatment (Filla 2012)
Allocation concealment Low risk Sealed envelopes containing the treatment assignment for each subject were
(selection bias) held by a member of the study team who was not involved in study assess-
ments. All envelopes remained sealed at the end of the study. Study personnel
involved in participant assessments (investigators and co-ordinators), partici-
pants and caregivers were blinded to the treatment assignment
Informed decisions.
Zesiewicz 2012 (Continued)
Blinding of participants Low risk Participants were blinded to treatment condition

mance bias)
All outcomes
Blinding of outcome as- Low risk All individuals involved in the assessments, including the investigators and
sessment (detection bias) participants, were blinded to the treatment assignment
All outcomes
Selective reporting (re- Unclear risk The 2nd period of the experiment, which was to include a cross-over compo-
porting bias) nent, was abandoned due to the high dropout rate observed in the initial peri-
od reported
Incomplete outcome data High risk Only 5 participants completed the placebo arm and 8 completed the vareni-
(attrition bias) cline arm of the study. Data were analysed for 9 participants in each group de-
All outcomes spite the large number of participant dropouts. The time points at which the
participants withdrew from the study were not stated, neither was the time at
which the final (end point) analyses were performed
ADL: activities of daily living

FARS: Friedreich Ataxia Rating Scale
ICA: idiopathic cerebellar ataxia
ICARS: International Cooperative Ataxia Rating Scale
ITT: intention-to-treat
L-5HT: L-hydroxytryptophan
rhuEPO: recombinant human erythropoietin
SARA: Scale for Assessment and Rating of Ataxia
SCA: spinocerebellar ataxia
SCD: spinocerebellar degeneration
SD: standard deviation
TRH-T: thyrotropin-releasing hormone tartrate
VAS: visual analogue scale
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Arnold 2006 No control group or randomisation of participants
Artuch 2002 No control group or randomisation of participants
Artuch 2006 Single case study
Boesch 2007 No control group or randomisation of participants
Boesch 2008 No control group or randomisation of participants. Open-label clinical pilot study
Bonnan 2008 No control group or randomisation
Botez 1996 Speech not included as an outcome measure
Botez 1997 Single case study
Broccoletti 2008 No control group or randomisation of participants
Informed decisions.
Study Reason for exclusion
Ershova 2007 No control group
Heo 2008 No control group
Ilg 2012 No randomisation or placebo
Lagedrost 2011 6-month extension of Lynch 2010, focused on cardiac outcomes
Meier 2012 No control group or randomisation of participants in the open label extension of Lynch 2010 and
Lagedrost 2011 (the subsequent 12 months)
Melancon 1982 No randomisation
Nakamura 2009 No control group or randomisation of participants
Ogawa 2003 No randomisation. Single-blinded only. Heterogenous group of spinocerebellar degeneration
Pineda 2008 No randomisation. Open-label design
Shimizu 1999 No control group or placebo
Sobue 1980 No control group or placebo
Strupp 2011 No relevant outcome measures included
Trouillas 1984 No randomisation
Trouillas 1997 Unclear clinical diagnosis. All participants presented with a sporadic form of pure cerebellar corti-
cal atrophy. Speech not reported as an outcome measure
Velasco-Sanchez 2011 No control group or randomisation of participants
Yabe 1999 No control group or randomisation of participants
Characteristics of ongoing studies [ordered by study ID]
EUCTR 2009-016317-20-IT
Trial name or title Pilot study to assess safety and tolerability of lithium on spinocerebellar ataxia of type 2 - lithium in
SCA2
Methods Double-blind, placebo-controlled, parallel-group, randomised pilot clinical trial
Participants Inclusion criteria: molecular diagnosis of SCA2, age > 18 years
Interventions Hard capsule oral lithium carbonate 300 mg or placebo
Outcomes Main objective: safety and tolerability of lithium in SCA2
Primary end point(s):
• serious and non serious adverse events

• safety laboratory parameters
Informed decisions.
EUCTR 2009-016317-20-IT (Continued)

Secondary objective: effect of lithium on clinical measures
Starting date 26 October 2009
Contact information Not provided
Notes —
EUCTR 2012-005312-26-DE
Trial name or title Sustained release 4-aminopyridine (Fampyra®) in cerebellar gait disorder
Methods Randomised, double-blind, placebo-controlled, cross-over trial
Participants Men or women aged 18 to 80 with a clinically evaluated diagnosis of cerebellar ataxia with at least 2
points on the SARA
Interventions Sustained released 4-aminopyridine (Fampyra) or placebo
Outcomes Primary outcomes:
1. Logarithmised gait variability at maximum walking speed (CVmax (%))

2. Logarithmised individual preferred walking speed (G_pref)
Secondary outcomes:
1. Gait variability at maximum walking speed at the end of the 12-week treatment phase
2. Difference in the (relative) change of the individual preferred walking speed at the end of the 12-
week treatment phase versus baseline
3. Quantitative description or comparison of the changes in various ataxia, mobility and quality of
life scores within the 2 treatment groups versus baseline (after 14 days, 12 weeks or follow-up visit)
4. Number of falls
5. Frequency of (severe) adverse effects
Starting date 18 March 2013
Contact information IFB LMU, Marchioninistr. 15, 81377, Munich, Germany. FACEG.studie@med.uni-muenchen.de
Hospital of the University of Munich
Notes —
Schulz 2009
Trial name or title 12-month European phase III clinical study of SNT-MC17/idebenone in the treatment of Friedreich's
ataxia: baseline neurology data and interim safety results
Methods Double-blind, placebo-controlled, multicentre study
Participants 232 people with Friedreich ataxia were randomised. Participants were aged 8 years and older.
Mean age was 30 years
Informed decisions.
Schulz 2009 (Continued)
Interventions Participants randomly assigned to placebo or to 1 of 3 body weight-adjusted doses of idebenone

(i.e. 180, 450 or 1350 mg/day for participants weighing ≤ 45 kg and 360, 900 or 2250 mg/day for par-
ticipants weighing > 45 kg)
Outcomes Efficacy end points include absolute change in ICARS score from baseline to week 52 (primary end
point), as well as changes in the FARS, left ventricular mass index, and other measures of cardiac
and neurological function
Starting date Not reported
Contact information Not reported
Notes This study was funded by Santhera Pharmaceuticals. Published abstract available
ECG: electrocardiogram
NYHA: New York Heart Association
SCA: spinocerebellar ataxia
APPENDICES
Appendix 1. NMD Register (CRS) search strategy

#1 friedreich or freidreich or "spinocerebellar ataxia*" or "cerebellar ataxia*" or "spinocerebellar degeneration*" or "degenerative
cerebellar" [REFERENCE] [STANDARD]
#2 "dentatorubral-pallidoluysian atrophy" or "myoclonic epilepsies" or "episodic ataxia*" [REFERENCE] [STANDARD]
#3 ataxia* and Charlevoix-Saguenay [REFERENCE] [STANDARD]
#4 arsacs or Marinesco-Sjogren [REFERENCE] [STANDARD]
#5 MeSH DESCRIPTOR Spinocerebellar Degenerations Explode All [REFERENCE] [STANDARD]
#6 Ataxia* and "oculomotor apraxia" [REFERENCE] [STANDARD]
#7 Ataxia* and "vitamin E deficiency" [REFERENCE] [STANDARD]
#8 "Ataxia telangiectasia" or Joubert NEAR syndrome* [REFERENCE] [STANDARD]
#9 Joubert NEAR syndrome* [REFERENCE] [STANDARD]
#10 ataxia* NEAR (hereditary or genetic*) [REFERENCE] [STANDARD]
#11 ataxia* NEAR autosomal [REFERENCE] [STANDARD]
#12 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 [REFERENCE] [STANDARD]
#13 speech or voice or vocal or dysarth* or dysphon* or anarth* or dyspros* [REFERENCE] [STANDARD]
#14 "activities of daily living" or "quality of life" [REFERENCE] [STANDARD]
#15 fars or sara or icars [REFERENCE] [STANDARD]
#16 #13 or #14 or #15 [REFERENCE] [STANDARD]
#17 #12 and #16 [REFERENCE] [STANDARD]
Appendix 2. CENTRAL search strategy

#1 " friedreich ataxia" or "freidreich ataxia" or "dentatorubral pallidoluysian atrophy" or arsacs or "Spinocerebellar Degeneration*" or
"Marinesco Sjogren"
#2 "cerebellar ataxia" or "cerebellar degeneration" or "spinocerebellar ataxia*" or "episodic ataxia*" or "Ataxia Telangiectasia"
#3 Myoclonic near Epileps*
#4 ataxia* and Charlevoix near Saguenay
#5 Ataxia* and oculomotor near apraxia
#6 Ataxia* and "vitamin E" near deficiency
#7 Joubert near syndrome
#8 ataxia* near (hereditary or genetic*)
#9 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#10 #1 or #2 or #3 or #4 or #5 or #6 or #7 or #8
#11 speech or articulat* or voice or vocal or communicat* or dysarth* or dysphon* or anarth* or dyspros*
#12 FARS or SARA or ICARS or "activities of daily living" or "quality of life"
#13 #11 or #12
#14 #10 and #13
Informed decisions.
Appendix 3. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to October Week 1 2013>
Search strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (387734)
2 controlled clinical trial.pt. (89736)
3 randomized.ab. (285393)
4 placebo.ab. (156181)
5 drug therapy.fs. (1760424)
6 randomly.ab. (198338)
7 trial.ab. (300539)
8 groups.ab. (1270218)
9 or/1-8 (3284645)
10 exp animals/ not humans.sh. (4050082)
11 9 not 10 (2796869)
12 (Friedreich$ ataxia or Freidreich$ ataxia).tw. or Friedreich Ataxia/ (2698)
13 spinocerebellar ataxia$.mp. or exp cerebellar Ataxias/ (9673)
14 (cerebellar ataxia$1 or spinocerebellar degeneration$1 or degenerative cerebellar).tw. (4270)
15 dentatorubral-pallidoluysian atrophy.mp. or Myoclonic Epilepsies, Progressive/ (495)
16 episodic ataxia$.mp. (390)
17 (ataxia$ and Charlevoix-Saguenay).mp. (99)
18 arsacs.mp. (70)
19 exp Spinocerebellar Degenerations/ or Marinesco-Sjogren.mp. (6420)
20 (Ataxia$ and oculomotor apraxia).mp. (168)
21 (Ataxia$ and vitamin E deficiency).mp. (207)
22 Ataxia Telangiectasia/ or Ataxia-telangiectasia.mp. (7467)
23 (Joubert adj5 syndrome$).mp. (476)
24 (ataxia$ adj5 (hereditary or genetic$)).mp. (1635)
25 (ataxia$ adj5 autosomal).mp. (1267)
26 or/12-25 (20850)
27 (speech or articulat$ or voice or vocal or communicat$).mp. (371122)
28 Speech/ (17897)
29 Voice Disorders/ or Voice/ (10517)
30 Vocal Cord Paralysis/ or Vocal Cords/ (11395)
31 (dysarth$ or dysphon$ or anarth$ or dyspros$).mp. (8780)
32 Dysarthria/ (1850)
33 Dysphonia/ (702)
34 Speech Disorders/ (9857)
35 exp "rehabilitation of speech and language disorders"/ (8688)
36 "Activities of Daily Living"/ (50732)
37 "Quality of Life"/ (119526)
38 (fars or sara or icars).tw. (1218)
39 or/27-38 (531229)
40 11 and 26 and 39 (181)
41 remove duplicates from 40 (167)
Appendix 4. EMBASE (OvidSP) search strategy

Database: EMBASE <1980 to 2013 Week 41>
Search strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (38658)
2 double-blind procedure.sh. (118100)
3 single-blind procedure.sh. (18340)
4 randomized controlled trial.sh. (357811)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (1006930)
6 trial.ti. (153871)
7 or/1-6 (1144144)
8 exp animal/ or exp invertebrate/ or animal.hw. or non human/ or nonhuman/ (20103289)
9 human/ or human cell/ or human tissue/ or normal human/ (14948140)
10 8 not 9 (5187786)
11 7 not 10 (1004080)
Informed decisions.
12 limit 11 to embase (768408)

13 (Friedreich$ ataxia or freidereich$ ataxia).mp. or Friedreich Ataxia/ (3533)
14 cerebellar ataxia/ or cerebellar ataxia.tw. (6821)
15 (spinocerebellar ataxia$ or spinocerebellar degeneration$).mp. or Spinocerebellar degeneration/ (5278)
16 degenerative cerebellar.tw. (82)
17 dentatorubral-pallidoluysian atrophy.mp. or myoclonus epilepsy/ (4909)
20 arsacs.mp. (95)
21 Marinesco-Sjogren.mp. (199)
24 Ataxia Telangiectasia/ or Ataxia-telangiectasia.mp. (6540)
28 or/13-25 (26177)
29 speech/ (29407)
30 dysphonia/ (5750)
31 voice/ (12713)
32 vocal cord/ (9089)
33 vocal cord paralysis/ (5764)
34 dysarthria/ (8738)
35 speech disorder/ (18605)
36 exp speech rehabilitation/ (12766)
37 (speech or articulat$ or voice or vocal or communicat$ or dysarth$ or dysphon$ or anarth$ or dyspros$).mp. (536778)
38 daily life activity/ (54451)
39 activities of daily living.tw. (18670)
40 (sara or fars or icars).tw. (1696)
41 or/29-40 (594658)
42 12 and 28 and 41 (65)
43 remove duplicates from 42 (65)
Appendix 5. CINAHL Plus (EBSCOhost) search strategy

14 October 2013, 7:55:00 AM
S32 S31 Limiters - Exclude MEDLINE 9

S31 S18 AND S27 AND S3065
S30 S28 OR S29233,568
S29 FARS or SARA or ICARS or activities of daily living or quality of life93,620
S28 (speech or articulat* or voice or vocal or communicat* or dysarth* or dysphon* or anarth* or dyspros*)144,347
S27 S19 or S20 or S21 or S22 or S23 or S24 or S25 or S261,180
S26 cerebellar ataxia* or spinocerebellar degeneration* or degenerative cerebellar326
S25 ataxia* N5 genetic*149
S24 ataxia* N5 hereditary29
S23 (Ataxia* and oculomotor apraxia) or (Ataxia* and vitamin E deficiency) or Ataxia telangiectasia or (ataxia* N5 autosomal)197
S22 episodic ataxia* or (ataxia* and Charlevoix-Saguenay) or arsacs or Marinesco-Sjogren or (Joubert N5 syndrome*)142
S21 Friedreich* ataxia or Freidreich* ataxia or spinocerebellar ataxia* or dentatorubral pallidoluysian atrophy or (Myoclon* Epilep*)623
S20 (MH "Epilepsy, Juvenile Myoclonic")12
S19 (MH "Ataxia Telangiectasia") OR (MH "Spinocerebellar Degenerations+")295
S18 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17632,216
S17 ABAB design*81
S16 TI random* or AB random*127,116
S15 ( TI (cross?over or placebo* or control* or factorial or sham? or dummy) ) or ( AB (cross?over or placebo* or control* or factorial or
sham? or dummy) )258,734
S14 ( TI (clin* or intervention* or compar* or experiment* or preventive or therapeutic) or AB (clin* or intervention* or compar* or
experiment* or preventive or therapeutic) ) and ( TI (trial*) or AB (trial*) )88,979
S13 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) )28,367
S12 ( TI (single* or doubl* or tripl* or trebl*) or AB (single* or doubl* or tripl* or trebl*) ) and ( TI (blind* or mask*) or AB (blind* or
mask*) )20,304
S11 PT ("clinical trial" or "systematic review")112,699
Informed decisions.
S10 (MH "Factorial Design")881

S9 (MH "Concurrent Prospective Studies") or (MH "Prospective Studies")216,259
S8 (MH "Meta Analysis")17,466
S7 (MH "Solomon Four-Group Design") or (MH "Static Group Comparison")32
S6 (MH "Quasi-Experimental Studies")6,241
S5 (MH "Placebos")8,399
S4 (MH "Double-Blind Studies") or (MH "Triple-Blind Studies")27,689
S3 (MH "Clinical Trials+")166,844
S2 (MH "Crossover Design")10,966
S1 (MH "Random Assignment") or (MH "Random Sample") or (MH "Simple Random Sample") or (MH "Stratified Random Sample") or (MH
"Systematic Random Sample")62,816
Appendix 6. PsycInfo (OvidSP) search strategy

Database: PsycINFO <1806 to October Week 2 2013>
Search strategy:
--------------------------------------------------------------------------------
1 ataxia/ (1908)
2 (friedreich$ ataxia or freidreich$ ataxia).mp. (263)
3 spinocerebellar ataxia.mp. (487)
4 Spinocerebellar degeneration.mp. (55)
5 (cerebellar ataxia or degenerative cerebellar).mp. (691)
6 myoclonus/ (616)
7 epilepsy/ (16675)
8 6 and 7 (234)
9 myoclon$ epilepsy.mp. (501)
10 dentatorubral-pallidoluysian atrophy.mp. (33)
13 arsacs.mp. (20)
14 Marinesco-Sjogren.mp. (10)
17 Ataxia telangiectasia.mp. (92)
21 or/1-5,8-20 (3015)
22 exp Oral Communication/ (26849)
23 exp vocalization/ (13458)
24 exp speech disorders/ (8996)
25 vocal cords/ (221)
26 (speech or articulat$ or voice or vocal or communicat$ or dysarth$ or dysphon$ or anarth$ or dyspros$).mp. (281719)
27 activities of daily living.mp. (9814)
28 (syllable$ or pronounc$).mp. (25558)
29 (sara or fars or icars or ataxia rating scale).mp. (1369)
30 or/22-29 (321645)
31 21 and 30 (502)
32 (random$ or rct or cct or factorial$ or crossover$ or cross over$ or cross-over$ or placebo$ or (doubl$ adj blind$) or (singl$ adj blind
$) or assign$ or allocat$ or volunteer$).tw. (234648)
33 31 and 32 (24)
Appendix 7. ERIC Dialog/Datastar search strategy

1 FRIEDREICH ADJ ATAXIA OR FRDA OR SPINOCEREBELLAR ADJ ATAXIA$
2 dentatorubral ADJ pallidoluysian ADJ atrophy
3 myclon$ ADJ epileps$
4 episodic ADJ ataxia$ OR arsacs OR Spinocerebellar ADJ Degeneration$ OR Marinesco ADJ Sjogren
5 Ataxia$ AND oculomotor ADJ apraxia
Informed decisions.
6 Ataxia$ AND vitamin ADJ E ADJ deficiency
7 Ataxia ADJ Telangiectasia
8 Joubert WITH syndrome$
9 ataxia$ WITH (hereditary OR genetic$ OR autosomal)
10 ataxia$ WITH Charlevoix ADJ Saguenay
11 1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8 OR 9 OR 10
12 speech OR articulat$ OR voice OR vocal OR communicat$ OR dysarth$ OR dysphon$ OR anarth$ OR dyspros$
13 11 AND 12
Appendix 8. ERIC (ProQuest) search strategy

(Friedreich ADJ ataxia OR freidreich ADJ ataxia OR FRDA OR spinocerebellar ADJ ataxia) OR (dentatorubral ADJ pallidoluysian ADJ atrophy
OR myclon$ ADJ epileps$) OR (episodic ADJ ataxia$ OR arsacs OR Spinocerebellar ADJ Degeneration$ OR Marinesco ADJ Sjogren OR Ataxia
$ AND oculomotor ADJ apraxia) OR (Ataxia$ AND vitamin ADJ E ADJ deficiency OR Ataxia ADJ Telangiectasia) OR (Joubert WITH syndrome$
OR ataxia$ WITH (hereditary OR genetic$ OR autosomal)) OR (ataxia$ WITH Charlevoix ADJ Saguenay OR cerebellar ataxia OR degenerative
cerebellar) AND (speech OR articulat$ OR voice OR vocal OR communicat$ OR dysarth$ OR dysphon$ OR anarth$ OR dyspros$ OR FARS
OR SARA OR ICARS OR activities of daily living OR quality of life)
Appendix 9. Linguistics & Language Behavior Abstracts

all(speech) AND all((ataxia OR friedreich)) OR all(spinocerebellar)
Appendix 10. Dissertation Abstracts

ataxia AND ab((dysarthria OR speech))
Appendix 11. ClinicalTrials.gov

ataxia AND (dysarthria OR speech)
Appendix 12. International Clinical Trials Registry Platform

ataxia AND (dysarthria OR speech)
CONTRIBUTIONS OF AUTHORS
APV developed the original protocol, reviewed the abstracts and full-length articles and wrote the first draft of the review. JF also reviewed
the abstracts. JF and MLP evaluated the full-length versions of the relevant articles and edited later versions of the review. The authors
developed the search strategy in concert with the Trials Search Co-ordinator of the Cochrane Neuromuscular Disease Review Group, Angela
Gunn, who ran the searches.
DECLARATIONS OF INTEREST
AV: no known conflicts of interest to declare.
JF: no known conflicts of interest to declare.
MLP: no known conflicts of interest to declare.
SOURCES OF SUPPORT
Internal sources
• None, Other.
External sources
• National Health and Medical Research Council, Australia.
Adam Vogel was supported by an Early Career Research Fellowship
Informed decisions.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The original protocol required that all participants have a genetically confirmed diagnosis to be included in this review. However, this
excluded all studies conducted prior to the discovery of relevant disease-specific genes. Therefore, we have included studies that were
conducted prior to gene discovery techniques (for example, before 1996 for Friedreich ataxia). We included interventions if they were
administered for a minimum of one week and a maximum of 12 months, instead of six months. We altered the timing of outcome measures
to include assessments conducted immediately post intervention. For short-term outcome measures, this change meant that the review
included assessments conducted immediately post intervention to one month post intervention.
Professor Bruce Murdoch retired from authorship and Matthew Poole replaced him.
INDEX TERMS
Medical Subject Headings (MeSH)

Friedreich Ataxia [complications] [*therapy]; Randomized Controlled Trials as Topic; Speech; Speech Disorders [drug therapy]
[etiology] [*therapy]; Spinocerebellar Degenerations [complications] [*therapy]
MeSH check words

Humans

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Cochrane

Treatment for speech disorder in Friedreich ataxia and other

Vogel AP, Folker J, Poole ML

Vogel AP, Folker J, Poole ML.

Treatment for speech disorder in Friedreich ataxia and other hereditary

Adam P Vogel1, Joanne Folker2, Matthew L Poole1

Editorial group: Cochrane Neuromuscular Group.

Data collection and analysis

PLAIN LANGUAGE SUMMARY

The evidence is up to date to October 2013.

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

Cochrane Database of Systematic Reviews

Filla 1988 reported 44 adverse effects for participants on

GRADE Working Group grades of evidence

1 Filla 1988 (n = 31) utilised a cross-over design.

Varenicline for speech disorder resulting from hereditary ataxia

Cochrane Database of Systematic Reviews

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Riluzole for speech disorder resulting from hereditary ataxias

Outcomes Illustrative comparative risks* (95% CI) Relative No of Qual- Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

Idebenone for speech disorder resulting from hereditary ataxias

Cochrane Database of Systematic Reviews

Outcomes Illustrative comparative risks* (95% CI) Relative No of Qual- Comments

Cochrane Database of Systematic Reviews

Cochrane Database of Systematic Reviews

Betamethasone (BETA) for speech disorder resulting from hereditary ataxias

Outcomes Illustrative comparative risks* (95% CI) Relative No of Qual- Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

1Speech disorder was measured on a subjective, clinician-derived severity rating scale.

Cochrane Database of Systematic Reviews

Outcomes Illustrative comparative risks* (95% CI) Relative No of Qual- Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Outcomes Illustrative compara- Relative No of Qual- Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

1Speech was measured on a subjective scale.

Cochrane Database of Systematic Reviews

α-tocopheryl quinone for speech disorder resulting from hereditary ataxia

Cochrane Database of Systematic Reviews

Outcomes Illustrative compar- Relative No of Qual- Comments

Cochrane Database of Systematic Reviews

GRADE Working Group grades of evidence

Cochrane Database of Systematic Reviews

BACKGROUND How the intervention might work

Figure 2. Study flow diagram.

Database Period searched Date searched Number of hits

Cochrane Neuromuscular Disease Group Up to 15 October 2013 15 October 2013 0

CENTRAL Up to 14 October 2013 14 October 2013 25

MEDLINE 1966 to October 2013 14 October 2013 96

EMBASE 1980 to October 2013 14 October 2013 75

CINAHL 1937 to October 2013 14 October 2013 35