Clinical efficacy and safety of lamotrigine monotherapy in newly diagnosed pediatric patients with epilepsy

Purpose : To verify the efficacy and safety of lamotrigine (LTG) monotherapy in newly diagnosed children with epilepsy. Methods : We prospectively enrolled 148 children who had undergone LTG monotherapy at our institution between September 2002 and June 2009. Twenty-nine patients were excluded: 19 due to incomplete data and 10 were lost to follow up. The data of the remaining 119 patients was analyzed. Results : We enrolled 119 pediatric epilepsy patients (aged 2.8-19.3 years&#59; 66 males and 53 females) in this study. Out of 119 patients, 29 (25.2%) had generalized epilepsy and 90 (74.8%) had partial epilepsy. The responses of seizure reduction were as follows: Seizure freedom (no seizure attack for at least 6 months) in 87/111 (78.4%, n=111) patients&#59; partial response (reduced seizure frequency compared to baseline) in 13 (11.7%) patients&#59; and persistent seizure in 11 (9.9%) patients. The seizure freedom rate was in 81.6% in patients with partial seizure (75.9% for complex partial seizure and 90.9% for benign rolandic epilepsy) and 44.8% in patients with generalized epilepsy (30.0% for absence seizure, 35.7% for juvenile myoclonic epilepsy patients, and 100.0% for idiopathic generalized epilepsy patients). Adverse reactions were reported in 17 (14.3%) patients, and 8 patients (6.7%) discontinued LTG because of rash and tic. No patient experienced severe adverse reaction such as Stevens-Johnson syndrome. Conclusion : LTG showed excellent therapeutic response and had few significant adverse effects. Our findings report may contribute in promoting the use of LTG monotherapy in epileptic children

The development of an online decision support tool for organizational readiness for change

BACKGROUND: Much importance has been placed on assessing readiness for change as one of the earliest steps of implementation, but measuring it can be a complex and daunting task. Organizations and individuals struggle with how to reliably and accurately measure readiness for change. Several measures have been developed to help organizations assess readiness, but these are often underused due to the difficulty of selecting the right measure. In response to this challenge, we will develop and test a prototype of a decision support tool that is designed to guide individuals interested in implementation in the selection of an appropriate readiness assessment measure for their setting. METHODS: A multi-phase approach will be used to develop the decision support tool. First, we will identify key measures for assessing organizational readiness for change from a recently completed systematic review. Included measures will be those developed for healthcare settings (e.g., acute care, public health, mental health) and that have been deemed valid and reliable. Second, study investigators and field experts will engage in a mapping exercise to categorize individual items of included measures according to key readiness constructs from an existing framework. Third, a stakeholder panel will be recruited and consulted to determine the feasibility and relevance of the selected measures using a modified Delphi process. Fourth, findings from the mapping exercise and stakeholder consultation will inform the development of a decision support tool that will guide users in appropriately selecting change readiness measures. Fifth, the tool will undergo usability testing. DISCUSSION: Our proposed decision support tool will address current challenges in the field of organizational change readiness by aiding individuals in selecting a valid and reliable assessment measure that is relevant to user needs and practice settings. We anticipate that implementers and researchers who use our tool will be more likely to conduct readiness for change assessments in their settings when planning for implementation. This, in turn, may contribute to more successful implementation outcomes. We will test this tool in a future study to determine its efficacy and impact on implementation processes

The burden of premature mortality of epilepsy in high-income countries: A systematic review from the Mortality Task Force of the International League Against Epilepsy

Since previous reviews of epidemiologic studies of premature mortality among people with epilepsy were completed several years ago, a large body of new evidence about this subject has been published. We aim to update prior reviews of mortality in epilepsy and to reevaluate and quantify the risks, potential risk factors, and causes of these deaths. We systematically searched the Medline and Embase databases to identify published reports describing mortality risks in cohorts and populations of people with epilepsy. We reviewed relevant reports and applied criteria to identify those studies likely to accurately quantify these risks in representative populations. From these we extracted and summarized the reported data. All population-based studies reported an increased risk of premature mortality among people with epilepsy compared to general populations. Standard mortality ratios are especially high among people with epilepsy aged <50 years, among those whose epilepsy is categorized as structural/metabolic, those whose seizures do not fully remit under treatment, and those with convulsive seizures. Among deaths directly attributable to epilepsy or seizures, important immediate causes include sudden unexpected death in epilepsy (SUDEP), status epilepticus, unintentional injuries, and suicide. Epilepsy-associated premature mortality imposes a significant public health burden, and many of the specific causes of death are potentially preventable. These require increased attention from healthcare providers, researchers, and public health professionals

EpiNet as a way of involving more physicians and patients in epilepsy research: Validation study and accreditation process

open185siObjective: EpiNet was established to encourage epilepsy research. EpiNet is used for multicenter cohort studies and investigator-led trials. Physicians must be accredited to recruit patients into trials. Here, we describe the accreditation process for the EpiNet-First trials. Methods: Physicians with an interest in epilepsy were invited to assess 30 case scenarios to determine the following: whether patients have epilepsy; the nature of the seizures (generalized, focal); and the etiology. Information was presented in two steps for 23 cases. The EpiNet steering committee determined that 21 cases had epilepsy. The steering committee determined by consensus which responses were acceptable for each case. We chose a subset of 18 cases to accredit investigators for the EpiNet-First trials. We initially focused on 12 cases; to be accredited, investigators could not diagnose epilepsy in any case that the steering committee determined did not have epilepsy. If investigators were not accredited after assessing 12 cases, 6 further cases were considered. When assessing the 18 cases, investigators could be accredited if they diagnosed one of six nonepilepsy patients as having possible epilepsy but could make no other false-positive errors and could make only one error regarding seizure classification. Results: Between December 2013 and December 2014, 189 physicians assessed the 30 cases. Agreement with the steering committee regarding the diagnosis at step 1 ranged from 47% to 100%, and improved when information regarding tests was provided at step 2. One hundred five of the 189 physicians (55%) were accredited for the EpiNet-First trials. The kappa value for diagnosis of epilepsy across all 30 cases for accredited physicians was 0.70. Significance: We have established criteria for accrediting physicians using EpiNet. New investigators can be accredited by assessing 18 case scenarios. We encourage physicians with an interest in epilepsy to become EpiNet-accredited and to participate in these investigator-led clinical trials.openBergin P.S.; Beghi E.; Sadleir L.G.; Brockington A.; Tripathi M.; Richardson M.P.; Bianchi E.; Srivastava K.; Jayabal J.; Legros B.; Ossemann M.; McGrath N.; Verrotti A.; Tan H.J.; Beretta S.; Frith R.; Iniesta I.; Whitham E.; Wanigasinghe J.; Ezeala-Adikaibe B.; Striano P.; Rosemergy I.; Walker E.B.; Alkhidze M.; Rodriguez-Leyva I.; Ramirez Gonzalez J.A.; D'Souza W.J.; Calle A.; Palacios C.; Cairns A.; Carney P.; Craig D.; Gill D.; Gupta S.; Lander C.; Laue-Gizzi H.; Hitchens N.; Kiley M.; Lawn N.; Reyneke E.; Riney K.; Tan M.; Tan M.; Thieban M.; Wong C.; van Rijckevorsel G.; Ferrari Strang A.G.; Gifoni A.; Helio L.; Monnerat B.; Brna P.; Donner E.; Jacques S.; Jette N.; McLachlan R.; Mohamed I.; Tran T.P.Y.; Bo X.; Fan S.; Guang Y.; Li M.; Wang K.; Zhang S.; Ladino L.; Christensen J.; Kӧlmel M.S.; Nikanorova M.; Uusitalo A.; Vieira P.; Auvin S.; Ediberidze T.; Gogatishvili N.; Jishkariani T.; Dennig D.; Grimmer A.; Michaelis R.; Schubert-Bast S.; Stephani C.; Stodieck S.; Vollbrandt M.; Zellner A.; Zafeiriou D.; Fogarasi A.; Halasz P.; Chaurasia R.N.; Jain S.; Nair R.; Passi P.; Rajadhyaksha S.; Sattaluri S.J.; Shah H.; Udani V.; Costello D.; Aguglia U.; Bartocci A.; Benna P.; Ferlazzo E.; Laino D.; Spalice A.; Zanchi C.; Ali A.; Lim K.S.; Ramirez A.; Anderson N.; Barber A.; Cariga P.; Cleland J.; Child N.; Davis S.; Dayal V.; Dickson C.; Doran J.; Duncan R.; Giri P.; Herd M.; Hutchinson D.; Jones B.; Kao J.; Kilfoyle D.; Mottershead J.; Muir C.; Nolan M.; Pereira J.; Ranta A.; Sadani S.; Simpson M.; Spooner C.; Timmings P.; Walker E.; Wei D.; Willoughby E.; Wong E.; Wu T.; Olusola T.; Mahmud H.; Mogul Z.; Espinoza J.; Vizarreta J.H.; Baeta E.M.; Teotonio R.; Jocic-Jakubi B.; Lukic S.; Korosec M.; Zgur T.; Eguilaz M.G.; Asztely F.; Sithinamsuwan P.; Anderson J.; Auce P.; Desurkar A.; Hamandi K.; Kelso A.; Sanchez V.; Sidra A.; Smith P.; Wehner T.; Winston G.; Andrade E.; Bensalem-Owen M.; Boudreau M.; Caller T.; Chapman K.; Chari G.; Davis K.; Droker B.; El-Hagrassy M.; Eliashiv D.; Eze C.; Heck C.; Kabir A.; Kolesnik D.; Lam A.; Lopez J.; Maamoon T.; Cohen J.M.; Maganti R.; Nwankwo C.; Park K.; Proteasa S.; Sandok E.; Seinfield S.; Toub J.; Wirrell E.; Arbildi M.; Thien T.T.Bergin, P. S.; Beghi, E.; Sadleir, L. G.; Brockington, A.; Tripathi, M.; Richardson, M. P.; Bianchi, E.; Srivastava, K.; Jayabal, J.; Legros, B.; Ossemann, M.; Mcgrath, N.; Verrotti, A.; Tan, H. J.; Beretta, S.; Frith, R.; Iniesta, I.; Whitham, E.; Wanigasinghe, J.; Ezeala-Adikaibe, B.; Striano, P.; Rosemergy, I.; Walker, E. B.; Alkhidze, M.; Rodriguez-Leyva, I.; Ramirez Gonzalez, J. A.; D'Souza, W. J.; Calle, A.; Palacios, C.; Cairns, A.; Carney, P.; Craig, D.; Gill, D.; Gupta, S.; Lander, C.; Laue-Gizzi, H.; Hitchens, N.; Kiley, M.; Lawn, N.; Reyneke, E.; Riney, K.; Tan, M.; Tan, M.; Thieban, M.; Wong, C.; van Rijckevorsel, G.; Ferrari Strang, A. G.; Gifoni, A.; Helio, L.; Monnerat, B.; Brna, P.; Donner, E.; Jacques, S.; Jette, N.; Mclachlan, R.; Mohamed, I.; Tran, T. P. Y.; Bo, X.; Fan, S.; Guang, Y.; Li, M.; Wang, K.; Zhang, S.; Ladino, L.; Christensen, J.; Kӧlmel, M. S.; Nikanorova, M.; Uusitalo, A.; Vieira, P.; Auvin, S.; Ediberidze, T.; Gogatishvili, N.; Jishkariani, T.; Dennig, D.; Grimmer, A.; Michaelis, R.; Schubert-Bast, S.; Stephani, C.; Stodieck, S.; Vollbrandt, M.; Zellner, A.; Zafeiriou, D.; Fogarasi, A.; Halasz, P.; Chaurasia, R. N.; Jain, S.; Nair, R.; Passi, P.; Rajadhyaksha, S.; Sattaluri, S. J.; Shah, H.; Udani, V.; Costello, D.; Aguglia, U.; Bartocci, A.; Benna, P.; Ferlazzo, E.; Laino, D.; Spalice, A.; Zanchi, C.; Ali, A.; Lim, K. S.; Ramirez, A.; Anderson, N.; Barber, A.; Cariga, P.; Cleland, J.; Child, N.; Davis, S.; Dayal, V.; Dickson, C.; Doran, J.; Duncan, R.; Giri, P.; Herd, M.; Hutchinson, D.; Jones, B.; Kao, J.; Kilfoyle, D.; Mottershead, J.; Muir, C.; Nolan, M.; Pereira, J.; Ranta, A.; Sadani, S.; Simpson, M.; Spooner, C.; Timmings, P.; Walker, E.; Wei, D.; Willoughby, E.; Wong, E.; Wu, T.; Olusola, T.; Mahmud, H.; Mogul, Z.; Espinoza, J.; Vizarreta, J. H.; Baeta, E. M.; Teotonio, R.; Jocic-Jakubi, B.; Lukic, S.; Korosec, M.; Zgur, T.; Eguilaz, M. G.; Asztely, F.; Sithinamsuwan, P.; Anderson, J.; Auce, P.; Desurkar, A.; Hamandi, K.; Kelso, A.; Sanchez, V.; Sidra, A.; Smith, P.; Wehner, T.; Winston, G.; Andrade, E.; Bensalem-Owen, M.; Boudreau, M.; Caller, T.; Chapman, K.; Chari, G.; Davis, K.; Droker, B.; El-Hagrassy, M.; Eliashiv, D.; Eze, C.; Heck, C.; Kabir, A.; Kolesnik, D.; Lam, A.; Lopez, J.; Maamoon, T.; Cohen, J. M.; Maganti, R.; Nwankwo, C.; Park, K.; Proteasa, S.; Sandok, E.; Seinfield, S.; Toub, J.; Wirrell, E.; Arbildi, M.; Thien, T. T

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Sudden unexpected death in epilepsy: is carbamazepine implicated?

Sudden unexpected death in epilepsy (SUDEP) has been recognised for centuries. The precise frequency of occurrence is not well defined. Education of medical professionals is needed, so that death certificates and coronial inquests may appropriately, correctly and consistently record SUDEP as the case of death. Correct identification will then allow further investigation of this misunderstood, and often ignored, epilepsy complication. SUDEP incidence may be increasing, either as a result of increased recognition, or possibly due to a real increase in incidence. All currently available antiepileptic drugs (AEDs) have been associated with SUDEP, and current opinion assumes that the relative proportion of patients suffering SUDEP is representative of average AED usage type for a particular time and locality, however, recently analysed data suggest a strong bias towards carbamazepine. A review of Cardiff Epilepsy Unit data shows that carbamazepine was disproportionately represented in patients suffering SUDEP. In this series, 11 of the 14 SUDEP patients were taking carbamazepine at the time of death. This was calculated as 79% of all patients, compared to average carbamazepine usage by all other Cardiff Epilepsy Unit patients of 38%. The data also indicate that one patient was not taking any drug therapy, and died during his first seizure, reducing the number of evaluable ‘drug usage’ patients to 13, and increasing the proportion taking carbamazepine at the time of death to 85%, (P < 0.01). Possible mechanisms include carbamazepine induced lengthening of the ECG Q-T interval combined with a mild pro-arrhythmic effect of epileptic seizure discharges, and consequent transient cardiac instability leading to arrhythmic death. Or alternatively, excessive post-seizure brainstem inhibition might result in blunting or transient abolition of central hypoxic and hypercarbic respiratory drive, with consequent post-ictal respiratory arrest, subsequent exacerbation of hypoxia, further cardiac destabilisation and death due to hypoxia/failed re-establishment of respiration and terminal cardiac arrhythmia. Current knowledge about SUDEP remains poor. Education is needed so that case ascertainment can be correctly documented. Delineation of the precise mechanisms involved should lead to definitive prevention strategies. Evaluation of carbamazepine as a significant causative factor in SUDEP is also needed