Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy

Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na v) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing identified hemi- and heterozygous variants in the N-terminal domain of the A isoform of FHF2 (FHF2A). The X-linked FHF2 gene (also known as FGF13) has alternative first exons which produce multiple protein isoforms that differ in their N-terminal sequence. The variants were located at highly conserved residues in the FHF2A inactivation particle that competes with the intrinsic fast inactivation mechanism of Na v channels. Functional characterization of mutant FHF2A co-expressed with wild-type Na v1.6 (SCN8A) revealed that mutant FHF2A proteins lost the ability to induce rapid-onset, long-term blockade of the channel while retaining pro-excitatory properties. These gain-of-function effects are likely to increase neuronal excitability consistent with the epileptic potential of FHF2 variants. Our findings demonstrate that FHF2 variants are a cause of infantile-onset developmental and epileptic encephalopathy and underline the critical role of the FHF2A isoform in regulating Na v channel function

The SANAD II study of the effectiveness and cost-effectiveness of levetiracetam, zonisamide, or lamotrigine for newly diagnosed focal epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Levetiracetam and zonisamide are licensed as monotherapy for patients with focal epilepsy, but there is uncertainty as to whether they should be recommended as first-line treatments because of insufficient evidence of clinical effectiveness and cost-effectiveness. We aimed to assess the long-term clinical effectiveness and cost-effectiveness of levetiracetam and zonisamide compared with lamotrigine in people with newly diagnosed focal epilepsy. Methods: This randomised, open-label, controlled trial compared levetiracetam and zonisamide with lamotrigine as first-line treatment for patients with newly diagnosed focal epilepsy. Adult and paediatric neurology services across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked focal seizures. Participants were randomly allocated (1:1:1) using a minimisation programme with a random element utilising factor to receive lamotrigine, levetiracetam, or zonisamide. Participants and investigators were not masked and were aware of treatment allocation. SANAD II was designed to assess non-inferiority of both levetiracetam and zonisamide to lamotrigine for the primary outcome of time to 12-month remission. Anti-seizure medications were taken orally and for participants aged 12 years or older the initial advised maintenance doses were lamotrigine 50 mg (morning) and 100 mg (evening), levetiracetam 500 mg twice per day, and zonisamide 100 mg twice per day. For children aged between 5 and 12 years the initial daily maintenance doses advised were lamotrigine 1·5 mg/kg twice per day, levetiracetam 20 mg/kg twice per day, and zonisamide 2·5 mg/kg twice per day. All participants were included in the intention-to-treat (ITT) analysis. The per-protocol (PP) analysis excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analysis included all participants who received one dose of any study drug. The non-inferiority limit was a hazard ratio (HR) of 1·329, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on lamotrigine. The trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 990 participants were recruited between May 2, 2013, and June 20, 2017, and followed up for a further 2 years. Patients were randomly assigned to receive lamotrigine (n=330), levetiracetam (n=332), or zonisamide (n=328). The ITT analysis included all participants and the PP analysis included 324 participants randomly assigned to lamotrigine, 320 participants randomly assigned to levetiracetam, and 315 participants randomly assigned to zonisamide. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission versus lamotrigine (HR 1·18; 97·5% CI 0·95–1·47) but zonisamide did meet the criteria for non-inferiority in the ITT analysis versus lamotrigine (1·03; 0·83–1·28). The PP analysis showed that 12-month remission was superior with lamotrigine than both levetiracetam (HR 1·32 [97·5% CI 1·05 to 1·66]) and zonisamide (HR 1·37 [1·08–1·73]). There were 37 deaths during the trial. Adverse reactions were reported by 108 (33%) participants who started lamotrigine, 144 (44%) participants who started levetiracetam, and 146 (45%) participants who started zonisamide. Lamotrigine was superior in the cost-utility analysis, with a higher net health benefit of 1·403 QALYs (97·5% central range 1·319–1·458) compared with 1·222 (1·110–1·283) for levetiracetam and 1·232 (1·112, 1·307) for zonisamide at a cost-effectiveness threshold of £20 000 per QALY. Cost-effectiveness was based on differences between treatment groups in costs and QALYs. Interpretation: These findings do not support the use of levetiracetam or zonisamide as first-line treatments for patients with focal epilepsy. Lamotrigine should remain a first-line treatment for patients with focal epilepsy and should be the standard treatment in future trials. Funding: National Institute for Health Research Health Technology Assessment programme

The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Background: Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy. Methods: We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64). Findings: 520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of −0·040 (95% central range −0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of £20 000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years. Interpretation: Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate. Funding: National Institute for Health Research Health Technology Assessment Programme

Review of the genus Sparasion Latreille, 1802 (Hymenoptera: Platygastroidea: Sparasionidae) of the Oriental region with descriptions of new species from India

Abstract Background The genus Sparasion, endoparasitoids of Tettigoniidae, occur in the Nearctic, Palearctic, Afrotropical and Oriental regions. It is absent in the Neotropics and Australasia. Of the thirteen species found in the Oriental region only a single species is from India. Results Two new species groups - Sparasion bilahari species group and Sparasion manavati species group - are proposed for species from the Oriental region. Thirty-six species are described and illustrated of which twenty-four are new: Sparasion albopilosellus Cameron, 1906 (Pakistan); S. bhairavi Veenakumari, sp. n. (India); S. bhupali Veenakumari, sp. n. (India); S. bihagi Veenakumari, sp. n. (India); S. bilahari Veenakumari, sp. n. (India); S. cellularis Strand, 1913 (Taiwan); S. coconcus Kozlov and Lê, 2000 (Vietnam); S. coeruleus Kieffer, 1905 (Sumatra); S. cullaris Kozlov and Lê, 2000 (Vietnam); S. darbari Veenakumari, sp. n. (India); S. deepaki Veenakumari, sp. n. (India); S. domes Kozlov and Lê, 2000 (Vietnam); S. elbakyanae Veenakumari, sp. n. (India); S. formosus Kieffer, 1910 (Taiwan); S. hindoli Veenakumari, sp. n. (India); S. kalyani Veenakumari, sp. n. (India); S. kanakangi Veenakumari, sp. n. (India); S. karivadana Veenakumari, sp. n. (India); S. lividus Johnson, Masner & Musetti, 2008 (Philippines); S. manavati Veenakumari, sp. n. (India); S. meghmalhari Veenakumari, sp. n. (India); S. micromerus Kozlov and Lê, 2000 (Vietnam); S. pahadi Veenakumari, sp. n. (India); S. philippinensis Kieffer, 1913 (Philippines); S. ratnangi Veenakumari, sp. n. (India); S. rupavati Veenakumari, sp. n. (India); S. salagami Veenakumari, sp. n. (India); S. shulini Veenakumari, sp. n. (India); S. sinensis Walker, 1852 (China); S. sivaranjini Veenakumari, sp. n. (India); S. syamalangi Veenakumari, sp. n. (India); S. todi Veenakumari, sp. n. (India); S. travancoricus Mani and Sharma, 1981 (India); S. vanaspati Veenakumari, sp. n. (India); S. visvambari Veenakumari, sp. n. (India) and S. zeelafi Veenakumari, sp. n. (India). Keys to Oriental species of Sparasion are furnished. Intrasexual colour morphs among females of Sparasion is reported. Lectotype is designated for Sparasion cellularis Strand. Conclusions Twenty-four new species are added to the Indian fauna of Sparasion. Previously described species of Oriental Sparasion are redescribed and illustrated. Keys are furnished for all Oriental species

Patient Perspectives on Innovative Telemonitoring Enhanced Care Program for Chronic Heart Failure (ITEC-CHF): Usability Study

BackgroundTelemonitoring enables care providers to remotely support outpatients in self-managing chronic heart failure (CHF), but little is known about the usability and patients’ willingness to engage with this technology. ObjectiveThis study aims to evaluate feedback from patients with CHF following participation in the Innovative Telemonitoring Enhanced Care program for CHF (ITEC-CHF) study. MethodsThe telemonitoring intervention consisted of three components: remote weight monitoring, structured telephone support, and nurse-led collaborative care. Participants were provided with electronic weighing scales (W550; ForaCare), and a computer tablet (Galaxy Tab A; Samsung). They were asked to weigh themselves on the provided scales daily. Telemonitoring was integrated with a personal assistance call service and a nurse care service according to their workflows in usual care. Feedback on the usability of ITEC-CHF was collected via survey from study participants following 6 months of receiving telemonitoring care for their body weight. Survey responses were provided on a 5-point Likert scale and through open-ended questions to determine participants’ perceived benefits and barriers to using ITEC-CHF. ResultsA total of 67 participants (49/67, 73% male), with a mean age of 69.8 (SD 12.4) years completed the survey. The majority of participants agreed or strongly agreed that the ITEC-CHF program was easy to use (61/67, 91%), easy to navigate (51/65, 78%), useful (59/65, 91%), and made them feel more confident in managing their weight (57/67, 85%). Themes related to participants’ perceptions of telemonitoring included increased support for early intervention of clinical deterioration, improved compliance to daily weighing, a sense of reassurance, and improved self-care and accountability, among others. ConclusionsITEC-CHF was rated highly on usability and was well accepted by users as part of their routine self-management activities. Participants were willing to use telemonitoring because they perceived a broad spectrum of benefits for CHF management. Trial RegistrationAustralian New Zealand Clinical Trial Registry ID ACTRN 12614000916640; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=366691