Table 1 Clinical trials involving RTT patients with commentary relating to the specific domains of EBAD
Authors | Na | Duration (months) | Design | Intervention | Physiological Measurement(s) of Autonomic Function | Outcome Measures | Comments# | Reference |
|---|---|---|---|---|---|---|---|---|
Mancini et al. (2018) | 36 (26) | 6 | Randomised multicentre, placebo controlled double-blind | Desipramine | • ECG • AHI polysomnography • Respiration rate • Oxygen desaturation | Primary: • Change in AHI at 6 months from baseline Secondary: • CSS • SSI • Number of apnoeas • Number of hypopneas • Oxygen desaturation | No significant differences between groups (high dose, low dose or placebo) were observed in the outcome measures (AHI, breathing patterns, CSS or SSI) from baseline to 6 months. | [134] |
Downs et al. (2018) | 12 | 6b | Modified stepped wedge individually randomised controlled trial | Environmental enrichment | N/A | Primary: • Change from baseline in RSGMS Secondary: • Blood levels of BDNF protein • BMI • Sleep quality as measured using the DIMS subscale of the parent rated SDSC. • Mood as measured using the mood subscale of the RSBQ | • After 6 months of treatment, the enriched environment accounted for improvements in gross motor skills and elevated blood BDNF levels. • No change from baseline in BMI, sleep quality or mood. | [133] |
O’Leary et al. (2018) | 30 (29) | 18c | Randomised placebo controlled double-blind crossover | IGF-1 (full length) | Bioradio | Primary: • ADAMS • SA subscale • RSBQ • F/A subscale • PTSVAS top three concerns • CGI • PGI • Kerr (overall severity scale) Secondary: • Additional ADAMS subscales • additional RSBQ subscales • ABC-C subscales • MSEL • Vineland-II • CSBS-DP • Cardiorespiratory biomarkers | No significant improvements were noted between treatment groups | [132] |
Glaze et al. (2017) | 56d | 0.5–1 | Randomised Phase 2, placebo controlled double-blind | Trofinetide (IGF-1 tripeptide analogue) | • EEG • Electromyography • Oxygen desaturation • HRV • Respiratory rate variability | • Modified apnoea index score • ABC-C • MBA • RSSS • CGI-I • VAS | • Efficacy was demonstrated for trofinetide (Day 26 for 70 mg/kg treatment group, n = 17) in comparison to placebo for core features. • Effect sizes (with CI): ➢ CGI-I: − 0.554 (− 1.34, 0.23) ➢ Caregiver Top 3 Concerns: − 0.63 (− 1.42, 0.16) ➢ MBA change index: − 0.607 (− 1.39, 0.18) | [131] |
Smith-Hicks et al. (2017) | 38e | 6 | Randomised open-label | Dextromethorphan | EEG | • Cognitive status: ➢ MSEL ➢ VABS • Behavioural characterisation: ➢ Parent-completed ABC–Community Version ➢ *SSI ➢ RSSS • Gait • EEG | Dose dependent improvements deemed to be of statistical significance were noted for clinical seizures, receptive language and behavioural hyperactivity; however, there was no statistically significant improvement in global severity as assessed by the RSSS. | [130] |
Yuge et al. 2017 | 4 | 10-24f | Pilot open-label | Ghrelin | Not measured | • SDCF to assess clinical and neurological parameters • BFMDRS score to assess dystonia • VAS | Following treatment, improvement in scores were noted for: • SDCF for Patient 1 (31 [baseline] to 29 [2 years]) and Patient 2 (20 [baseline] to 18 [10 months]) • BFMDRS for Patient 1 (108.5 [baseline] to 100 [2 years]) and Patient 2 (67 [baseline] to 54.5 [10 months]) • Change in baseline in VAS for dystonia, tremor and sympathetic vasomotor reflexes in patient 1 and 2. | [129] |
Nissenkorn et al. 2017 | 14 | 6 (planned) | Open-label (Phase 2) | Glatiramer Acetate | Noninvasive respiratory inductance plethysmography | Primary: • Safety, tolerability of treatment • Decrease in epileptiform activity Secondary: • Seizure frequency • Improvement in respiratory dysfunction • Improvement in core features assessed by Kerr and Naidu validated severity scores) | Study was terminated due to treatment related serious adverse events in four patients. | [128] |
Djukic et al. (2016) | 10 | 6 | Open-label (Phase 2) | Glatiramer Acetate | • Xltek, Sleep Monitoring • Tobii T300 Eye Tracker • EEG | Primary: • Change in gait velocity (primary) Secondary: • Change in respiratory and cognitive functions, • Change in QOL measures (assessed using Child Health Questionnaire-P50) and • Change in EEG parameters | No statistically significant changes in QOL were observed, however, following glatiramer acetate treatment, improvements were noted for: • Gait velocity (13–95% improvement [p = 0.03]) • Memory and breath holding index (p ≤ 0.03) | [127] |
Fabio et al. (2016) | 34g | N/A | Observational | Cognitive training | • Eye-tracking • EEG | Functional and cognitive descriptive of sample using functional scales, matrices, eye tracking and EEG assessment. | Longer term (5 days) cognitive training appears to improve behaviour and brain parameters in RTT patients. | [126] |
Pini et al. (2016) | 10 | 6 | Open-label | IGF-1 (full length) | EEG | • ISS • RSS | Significant improvements seen in ISS (p = 0.0106) and RSS (p = 0.0274) outcome measures for the treatment group. | [125] |
Khwaja et al. (2014) | 12 | 1 MAD 5 OLEh | Open-label (Phase 1) | IGF-1 (full length) | • BioRadio • EEG | • Apnoea Index • Hyperventilation Index • MBA • RSBQ • ADAMS • EEGs | Following IGF-1 treatment, improvements were noted for: • Apnoea from Pre-MAD to Post-OLE (Apnoea index −7.12 ± 4.58 [mean ± SE]) • RSBQ (fear/anxiety subscale: − 0.79 [mean difference from visit 1 of OLE to visit 5 of OLE]), • ADAMS (social avoidance subscale: − 1.44 [mean difference from visit 1 of OLE to visit 5 of OLE]), • Reversal of right-sided alpha band frontal EEG symmetry | [124] |
Signorini et al. (2014) | 24i | 12 | Randomised, controlled study | ω-3 PUFAs | N/A | Examination of erythrocyte fatty acid profile | Improvements seen in ω-6/ω-3 ratio, serum lipid profiles as well as normalisation of inflammatory markers and reduction in bone hypodensity and PUFS peroxidation following ω-3 PUFA supplementation compared to the untreated group. | [123] |
Maffei et al. (2014) | 66j | 12 | Randomised, placebo controlled single-blind | ω-3 PUFAs | Echocardiography | Measurement of oxidative stress biomarkers and ECG parameters | Improvements were noted in biventricular myocardial systolic parameters following ω-3 PUFAs treatment in comparison to placebo. | [122] |
Hagebeuk et al. (2013) | 10 | 26 | Randomised, placebo controlled, double-blind crossover | Folinic acid | N/A | Measurement of CSF, folate metabolite and SAH/SAM ratio | N/A | [121] |
De Felice et al. (2012) | 20 | 6 | Randomised, placebo controlled single-blind | ω-3 PUFAs | Respiratory polygraphy using Somnowatch | Primary • CSS • Respiratory dysfunction • Video clips pre-& post treatment Secondary • Reduction in oxidative stress markers following treatment | Although respiratory dysfunction improved after 6 months of treatment no significant changes were detected in autonomic symptoms as assessed by the CSS. | [120] |
Pini et al. (2012) | 6 | 6 | Open-label pilot | IGF-1 (tripeptide form) | • Neuroscope • ECG • EEG | • Autonomic parameters evaluated were cardiac vagal tone, HR, transcutaneous blood gases, and trends in respiration • ISS parameters (growth and development, locomotor apparatus, locomotor ability, cortical and autonomic functions) • EEG measurements | Safety and tolerability study – no statistically significant changes were reported in cardiac function (ECG, HR and vagal tone) or in all ISS parameters during IGF-1 treatment. | [119] |
Hagebeuk et al. (2012) | 8 | 26 | Randomised, placebo controlled double-blind crossover | Folinic acid | N/A | • Plasma folate measurement • MBA • Hand Apraxia Scale • Parental Overall Well-Being Index | No statistically significant differences were found for neurological features, Hand Apraxia Scale or the MBA | [118] |
Hagebeuk et al. (2011) | 12 | 24 | Randomised, placebo controlled, double-blind crossover | Folinic acid | EEG | Change in seizure frequency and EEG | Benefits only noted in 3 patients on folinic acid. | [117] |
Freilinger et al. (2011) | 21k | 13 | Double-blind, randomised, placebo-controlled crossover | Creatine | N/A | • Change in global DNA methylation • Change in RTT specific symptom score as defined by MBA | No statistically significant changes in either the total or sub-scores of the MBA | [116] |
Signorini et al. (2011) | 42l | 12 | Open-label pilot | ω-3 PUFAs | N/A | Measurement of oxidative stress biomarkers | N/A | [115] |
Leoncini et al. (2011) | 42 | 12 | Open-label pilot | ω-3 PUFAs | N/A | Measurement of oxidative stress biomarkers | N/A | [114] |
Temudo et al. (2009) | 25 | 6 | Open-label in patients with low levels of folate metabolite | Folinic acid | N/A | Measurement of folate metabolites and CSF neurotransmitters | N/A | [113] |
Glaze et al. (2009) | 73 (68) | 12 | Randomised double-blind, placebo-controlled | Folate–betaine | Polygraphic measurements of breathing patterns, hand stereotypies and qualitative EEG | • Growth parameters (weight, height, BMI, and head circumference • EEG • MBA • Parent questionnaire | No objective improvements reported, however, subjective improvement based on a parent questionnaire was noted for the < 5 years age group. | [112] |
Wilfong & Schultz (2006) | 7 | 12 | Case series | Adjunctive vagus nerve stimulation (VNS) for treatment of epilepsy | Vagus nerve stimulation device | • Seizure frequency • Effect of VNS therapy on caregiver reported hyperventilation, breath holding, swallowing dysfunction, mood and communication. | • Improvements were noted in seizure frequency and in alertness. • No significant change in either mood or communication parameters following VNS therapy. | [111] |
Guideri et al. (2005) | 10m | 6–18 months (follow-up) | Randomised blinded study | Acetyl-L-carnitine | ECG parameters | • Heart rate variability • QTc interval • QTc dispersion | Increased heart rate variability was observed in the treatment group. | [110] |
Gorbachevskaya et al. (2001) | 9 | 20–40 daysn | Open-label pilot | Cerebrolysin | EEG | Quantitative EEG to monitor motor and cortical functions. | Modest improvements in motor and higher cortical functions in patients treated with cerebrolysin. | [109] |
Ellaway et al. (2001) | 21o | 6 | Open-label | L-carnitine | N/A | • RS: SSI • Hand Apraxia Scale • 7 day-night sleep diary • SF-36 Health Survey | Improvements noted in sleep efficiency (P = 0.027), expressive speech (P = 0.011), communication skills (P = 0.004) and energy levels (P < 0.005) in the treatment group in comparison to the control group. | [108] |
Ellaway et al. (1999) | 35 | 6 | Randomised placebo controlled double-blind crossover | L-carnitine | N/A | • MBA • Hand Apraxia Scale • Patient Well-Being Index | • No measurement of autonomic function. • Small improvements in patients’ well-being and hand apraxia scale in the L-carnitine treatment group. | [107] |
McArthur and Budden (1998) | 9 | 2.5 | Randomised placebo controlled double-blind crossover | Melatonin | Actigraphy (measures of sleep parameters) | Sleep parameters | • Melatonin decreased sleep onset (19.1 ± 5.3 min [mean ± SE]) in comparison to baseline (42.1 ± 12.0 min [mean ± SE]). • Other improvements were noted in total sleep time and sleep efficiency. | [106] |
Stenbom et al. (1998) | 12 | ~ 3-5p | Open-label pilot | Lamotrigine | EEG | • Seizure frequency • Motor skills • Safety and tolerability monitoring | Some improvements were noted in with lamotrigine regarding seizure frequency, alertness and concentration. | [105] |
Percy et al. (1994) | 25q | 9 | Randomised placebo controlled double-blind crossover | Naltrexone | EEG polygraphy that assessed sleep, respiratory characteristics and hand stereotypies. | • Neurophysiological parameters (assessment of sleep, respiratory characteristics and hand stereotypies). • Measurement of CSF and β endorphin | • Statistically significant differences were noted for a higher awake minimum O2 saturation (P = 0.03) and less time spent on disordered breathing (P = 0.02) in the naltrexone treatment group in comparison to the placebo treatment group. • No changes in EEG and sleep characteristics between the treatment and placebo group. | [104] |
Nielsen et al. (1990) | 11r | ~ 6 | Randomised double-blind crossover | Tyrosine and tryptophan | EEG | • Parent interviews and observation forms to assess child behaviour. | No clinical improvement. | [103] |
Zappella (1990) | 10 | 4 | Placebo controlled double-blind partial crossover | Bromocriptine | N/A | • Portage guide items for the assessment of motor, social and cognitive skills. | • In the treatment group, improvements in Portage guide items for motor, social and cognitive activities were noted for 2 subjects and minor improvement in 1 subject. • 7 subjects showed no change to treatment. | [102] |
Haas et al. (1986) | 7 | 2–6 | Open-label uncontrolled treatment trial | Ketogenic diet | • EEG • Transthoracic impedance to assess respiratory characteristics (central apnoea). | Changes in: • EEG • Respiratory monitoring • Clinical laboratory values | Clinical improvements noted in: • Seizure control, • Respiratory function, • Behavioural and motor control. | [101] |