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OP53 – 2462: The role of mTOR inhibitors in TSC associated epilepsy
EUROPEAN JOURNAL O F PAEDIATRIC NEUROLOGY
of spasms on and between days 14 and 42. Analysis is by intention to treat. Results: 377 children were enrolled and early clinical outcome data will be available on 376 (1 case withdrew). 185 were allocated hormonal therapy and vigabatrin and 191 were allocated hormonal therapy alone. 133/185 (71.9%) on combination therapy versus 108/191 (56.6%) on hormonal therapy alone achieved a primary clinical response: treatment difference 15.3% (95% CI 5.4% to 25.2%, p=0.002). The treatment effect favouring combination therapy remained highly significant in a logistic regression analysis controlling for underlying aetiology, country of enrollment, whether hormonal therapy was randomized or not, and gender (Odds ratio 2.03, 95% CI 1.3 to 3.2, p=0.002). Treatment response was also significantly faster on combination therapy (median response time = 2 days, IQR 2–4 days) than hormonal therapy alone (median response time = 4 days, IQR 3–6 days, p<0.001). The electroclinical response will also be reported at the meeting. Conclusion: The ICISS trial shows that combination therapy of hormonal therapy + vigabatrin is associated with a more rapid clinical response and greater proportion of infants achieving spasm cessation than on hormonal therapy alone.
OP51 - 3033 Prednisolone or tetracosactide depot for infantile spasms – A meta-analysis from UKISS and ICISS J.P. Osborne, E. Hancock, S. Edwards, F.J.K. O’Callaghan. Dept of Paediatrics, Royal United Hospital, Bath and School for Health, University of Bath, Bath, UK Objective: To examine the relative efficacy of prednisolone and tetracosactide depot in the treatment of infantile spasms using data from trials where treatment had been randomly allocated. Prednisone trials (against ACTH) were not included since prednisone is an inactive compound that infants poorly convert to the active compound, Prednisolone. Methods: A meta-analysis of results from both UKISS and ICISS clinical trials. Both trials compared hormonal treatment alone (either Prednisolone or Tetracosactide Depot) to another treatment regime but had randomly allocated the hormonal treatment in all (UKISS) or some (ICISS) infants. Both trials used the same dosages: Prednisolone 10 mg qds increasing to 20 mg tds after 7 days if spasms continued or Tetracosactide depot 0.5 mg on alternate days increasing to 0.75 mg after 7 days if spasms continued. Cessation of spasms was defined as in UKISS: no visible spasms on Days 13 and 14. This outcome was also available for infants in ICISS where a more stringent definition was used. Results: 124 infants (53 in UKISS and 71 in ICISS) were randomly allocated either Prednisolone (64) or Tetracosactide depot (60). Results for all infants are available. Cessation of spasms was achieved in 43 (67%) of those allocated Prednisolone and in 45 (75%) of those allocated Tetracosactide depot. There is no significant difference between these outcomes (Treatment difference 7.8%, 95% CI: −8.7% to +24.3%; Chi-square 0.92 and p=0.34). Conclusion: When these two treatments are used as initial single treatments and where cessation of spasms is the outcome measure, there is no evidence that one treatment is better than the other.
OP52 - 2694 The ketogenic diet versus ACTH in the treatment of infantile spasms: A prospective randomised study A. Dressler, P. Trimmel-Schwahofer, E. Reithofer, G. Gröppel, A. Mühlebner, S. Samueli, K. Abraham, F. Benninger, M. Feucht. Department of Pediatrics and Adolescent Health, Medical University Vienna, Vienna, Austria Objective: The prognosis of infantile spasms (IS) is usually unfavorable with respect to treatment and developmental outcomes. The antiepileptic drugs (AEDs) most likely to be effective in the
19s (2015) S1 – S152
S17
short-term management (complete cessation of spasm and EEG normalization) are ACTH and Vigabatrin, but there is insufficient evidence that these drugs also improve long-term outcomes. Both drugs have shown serious (irreversible and in part lethal) side effects. The ketogenic diet (KD) is licensed for drug-resistant epilepsy including IS as second-line treatment. Aim of this randomized, prospective study was to evaluate the efficacy and tolerability of the KD compared with ACTH. Methods: All infants with IS referred to the Medical University of Vienna between June 2008 and September 2014 who were eligible for both treatments were included and randomized to either ACTH or the KD (liquid formula) after informed consent. When failure to the first treatment occurred (seizures and/or persistent hypsarrhyhtmia), patients were switched to the alternative treatment. Seizure and developmental outcomes as well as side effects were evaluated at 12 months after treatment initiation. Results: 32 children were randomized (16 ACTH/16 KD). 9/16 randomized to the KD became seizure free (56%), with recurrence of seizures in 3 (18%) after 6 months. 7 (44%) did not respond. 10 non-responders were then switched to ACTH and further 4 children became seizure free (40%). The KD was well tolerated. 10/16 patients randomized to ACTH (62%) became seizure free and 3 (18%) relapsed, 6 (38%) did not respond. 6 patients were then switched to the KD and one child became seizure free (16%). 14/16 children on ACTH children showed severe side effects. Conclusion: No differences in responder rates or in efficacy were observed between the KD and ACTH. However, compliance was better in the KD group and no severe side effects were observed.
OP53 - 2462 The role of mTOR inhibitors in TSC associated epilepsy S. Samueli, K. Abraham, A. Dressler, G. Gröppel, A. Mühlebner-Fahrngruber, M. Feucht. Division of Neonatology, Intensive Care Medicine and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria We evaluated prospectively the effect of Everolimus on epilepsy in children and adolescents with TSC treated with Everolimus for SEGA at our center. Methods: This is a retrospective analysis of prospectively collected data: included were patients ≤19 years with epilepsy, treated with Votubia, who had regular prospective follow-up every 3 months at the study center (clinical inspection and EEG, seizure diaries, blood sampling). Everolimus is orally administered once per day, starting with 4.5 mg/m2 and titration to achieve blood trough concentrations of 5–15 ng/ml. Response was defined as ≥50% reduction in seizure count. Results: We present pilot data of 12 patients (4 female, 8 male), with genetically confirmed diagnosis of TSC (3 TSC1, 9 TSC2 mutations). The median age at initiation of Votubia was 10 years (y) (range: 2–19 y). The median duration of epilepsy prior to treatment was 9.5 y (range: 1.75–16.75 y). The median number of AEDs prior to treatment was 1 (range: 1–3). The median seizure frequency prior to treatment was 30 seizures/month (range: 2–1470 seizures/month). 8/12 (66%) patients were responders. The median follow up after initiation of Everolimus was 13.5 months (range: 2–31 months). The median reduction in seizure frequency was 93% (range: 0–100%). Four patients became seizure free. The median number of AED after treatment was 1 (range: 1–2). The effect on seizure frequency was accompanied by significant developmental progress in all seizure free children. 4 patients were non-responders, one of them was incompliant. Side effects were observed in 7 patients (58%). The most common side effects were aphtae (7/7); 1 patient was hospitalized because of angina herpetica and pneumonia. In no case the Everolimus treatment had to be interrupted or withdrawn. Conclusions: Everolimus seems to be effective and safe in treating TSC associated epilepsy in pediatric patients (even in cases prior refractory to AEDs).
of spasms on and between days 14 and 42. Analysis is by intention to treat. Results: 377 children were enrolled and early clinical outcome data will be available on 376 (1 case withdrew). 185 were allocated hormonal therapy and vigabatrin and 191 were allocated hormonal therapy alone. 133/185 (71.9%) on combination therapy versus 108/191 (56.6%) on hormonal therapy alone achieved a primary clinical response: treatment difference 15.3% (95% CI 5.4% to 25.2%, p=0.002). The treatment effect favouring combination therapy remained highly significant in a logistic regression analysis controlling for underlying aetiology, country of enrollment, whether hormonal therapy was randomized or not, and gender (Odds ratio 2.03, 95% CI 1.3 to 3.2, p=0.002). Treatment response was also significantly faster on combination therapy (median response time = 2 days, IQR 2–4 days) than hormonal therapy alone (median response time = 4 days, IQR 3–6 days, p<0.001). The electroclinical response will also be reported at the meeting. Conclusion: The ICISS trial shows that combination therapy of hormonal therapy + vigabatrin is associated with a more rapid clinical response and greater proportion of infants achieving spasm cessation than on hormonal therapy alone.
OP51 - 3033 Prednisolone or tetracosactide depot for infantile spasms – A meta-analysis from UKISS and ICISS J.P. Osborne, E. Hancock, S. Edwards, F.J.K. O’Callaghan. Dept of Paediatrics, Royal United Hospital, Bath and School for Health, University of Bath, Bath, UK Objective: To examine the relative efficacy of prednisolone and tetracosactide depot in the treatment of infantile spasms using data from trials where treatment had been randomly allocated. Prednisone trials (against ACTH) were not included since prednisone is an inactive compound that infants poorly convert to the active compound, Prednisolone. Methods: A meta-analysis of results from both UKISS and ICISS clinical trials. Both trials compared hormonal treatment alone (either Prednisolone or Tetracosactide Depot) to another treatment regime but had randomly allocated the hormonal treatment in all (UKISS) or some (ICISS) infants. Both trials used the same dosages: Prednisolone 10 mg qds increasing to 20 mg tds after 7 days if spasms continued or Tetracosactide depot 0.5 mg on alternate days increasing to 0.75 mg after 7 days if spasms continued. Cessation of spasms was defined as in UKISS: no visible spasms on Days 13 and 14. This outcome was also available for infants in ICISS where a more stringent definition was used. Results: 124 infants (53 in UKISS and 71 in ICISS) were randomly allocated either Prednisolone (64) or Tetracosactide depot (60). Results for all infants are available. Cessation of spasms was achieved in 43 (67%) of those allocated Prednisolone and in 45 (75%) of those allocated Tetracosactide depot. There is no significant difference between these outcomes (Treatment difference 7.8%, 95% CI: −8.7% to +24.3%; Chi-square 0.92 and p=0.34). Conclusion: When these two treatments are used as initial single treatments and where cessation of spasms is the outcome measure, there is no evidence that one treatment is better than the other.
OP52 - 2694 The ketogenic diet versus ACTH in the treatment of infantile spasms: A prospective randomised study A. Dressler, P. Trimmel-Schwahofer, E. Reithofer, G. Gröppel, A. Mühlebner, S. Samueli, K. Abraham, F. Benninger, M. Feucht. Department of Pediatrics and Adolescent Health, Medical University Vienna, Vienna, Austria Objective: The prognosis of infantile spasms (IS) is usually unfavorable with respect to treatment and developmental outcomes. The antiepileptic drugs (AEDs) most likely to be effective in the
19s (2015) S1 – S152
S17
short-term management (complete cessation of spasm and EEG normalization) are ACTH and Vigabatrin, but there is insufficient evidence that these drugs also improve long-term outcomes. Both drugs have shown serious (irreversible and in part lethal) side effects. The ketogenic diet (KD) is licensed for drug-resistant epilepsy including IS as second-line treatment. Aim of this randomized, prospective study was to evaluate the efficacy and tolerability of the KD compared with ACTH. Methods: All infants with IS referred to the Medical University of Vienna between June 2008 and September 2014 who were eligible for both treatments were included and randomized to either ACTH or the KD (liquid formula) after informed consent. When failure to the first treatment occurred (seizures and/or persistent hypsarrhyhtmia), patients were switched to the alternative treatment. Seizure and developmental outcomes as well as side effects were evaluated at 12 months after treatment initiation. Results: 32 children were randomized (16 ACTH/16 KD). 9/16 randomized to the KD became seizure free (56%), with recurrence of seizures in 3 (18%) after 6 months. 7 (44%) did not respond. 10 non-responders were then switched to ACTH and further 4 children became seizure free (40%). The KD was well tolerated. 10/16 patients randomized to ACTH (62%) became seizure free and 3 (18%) relapsed, 6 (38%) did not respond. 6 patients were then switched to the KD and one child became seizure free (16%). 14/16 children on ACTH children showed severe side effects. Conclusion: No differences in responder rates or in efficacy were observed between the KD and ACTH. However, compliance was better in the KD group and no severe side effects were observed.
OP53 - 2462 The role of mTOR inhibitors in TSC associated epilepsy S. Samueli, K. Abraham, A. Dressler, G. Gröppel, A. Mühlebner-Fahrngruber, M. Feucht. Division of Neonatology, Intensive Care Medicine and Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria We evaluated prospectively the effect of Everolimus on epilepsy in children and adolescents with TSC treated with Everolimus for SEGA at our center. Methods: This is a retrospective analysis of prospectively collected data: included were patients ≤19 years with epilepsy, treated with Votubia, who had regular prospective follow-up every 3 months at the study center (clinical inspection and EEG, seizure diaries, blood sampling). Everolimus is orally administered once per day, starting with 4.5 mg/m2 and titration to achieve blood trough concentrations of 5–15 ng/ml. Response was defined as ≥50% reduction in seizure count. Results: We present pilot data of 12 patients (4 female, 8 male), with genetically confirmed diagnosis of TSC (3 TSC1, 9 TSC2 mutations). The median age at initiation of Votubia was 10 years (y) (range: 2–19 y). The median duration of epilepsy prior to treatment was 9.5 y (range: 1.75–16.75 y). The median number of AEDs prior to treatment was 1 (range: 1–3). The median seizure frequency prior to treatment was 30 seizures/month (range: 2–1470 seizures/month). 8/12 (66%) patients were responders. The median follow up after initiation of Everolimus was 13.5 months (range: 2–31 months). The median reduction in seizure frequency was 93% (range: 0–100%). Four patients became seizure free. The median number of AED after treatment was 1 (range: 1–2). The effect on seizure frequency was accompanied by significant developmental progress in all seizure free children. 4 patients were non-responders, one of them was incompliant. Side effects were observed in 7 patients (58%). The most common side effects were aphtae (7/7); 1 patient was hospitalized because of angina herpetica and pneumonia. In no case the Everolimus treatment had to be interrupted or withdrawn. Conclusions: Everolimus seems to be effective and safe in treating TSC associated epilepsy in pediatric patients (even in cases prior refractory to AEDs).