Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.

BACKGROUND: Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. METHODS: In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1-24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6-8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013-002195-40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. FINDINGS: Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6-8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1-16]) and antiseizure medication group (3 [IQR 2-11]; IRR 1·33, 95% CI 0·84-2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. INTERPRETATION: In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. FUNDING: National Institute for Health and Care Research.

Text integration processes in children with Childhood Epilepsy with Centro-Temporal Spikes.

Although Childhood Epilepsy with Centro-Temporal Spikes (CECTS) is considered a 'benign' form of epilepsy, word reading, listening comprehension, and reading comprehension difficulties have been reported. We examined two core skills for text comprehension, coherence monitoring and inference generation, in children with CECTS and compared performance with typically developing controls. Children with CECTS (n = 23; 9 females; mean age 9 y 0 m) and the comparison group (n = 38; 14 females; mean age 9 y 1 m) completed two tasks. For coherence monitoring they heard 24 narrative texts, 16 containing two inconsistent sentences, and responded to a yes/no question to assess identification of the inconsistency after each text; for inference making they heard 16 texts designed to elicit a target inference by integrating information in two sentences and responded to a yes/no question to assess generation of the inference. In both tasks there was a near condition, in which critical sentences were adjacent, and a far condition in which these sentences were separated by filler sentences. Accuracy to the question and the processing time for critical sentences in the text were measured. We used listening comprehension tasks to control for variation in word reading ability. Mixed effects analyses for each task revealed that children with CECTS show comparable levels of accuracy to age-matched peers in these tasks tapping two core text integration skills: detection of inconsistencies and generation of inferences. However, they take longer to process texts indicating a likely source of their listening and reading comprehension difficulties.

A homozygous GRIN1 null variant causes a more severe phenotype of early infantile epileptic encephalopathy.

Pathogenic variants in glutamate receptor, ionotropic, NMDA-1 (GRIN1) cause an autosomal dominant or recessive neurodevelopmental disorder with global developmental delay, with or without seizures (AD or AR GRIN1-NDD). Here, we describe a novel homozygous canonical splice site variant in GRIN1 in a 12-month-old boy with early infantile epileptic encephalopathy and severe global developmental delay. This represents only the second family with a homozygous predicted-null variant in GRIN1 reported to date. We review the published literature on AR GRIN1-NDD and find that the phenotype in our patient is much more severe than those seen with homozygous missense variants. A similarly severe phenotype of intractable epilepsy and infantile death has only been reported in one other family with a homozygous nonsense variant in GRIN1. We, therefore, propose that biallelic predicted-null variants in GRIN1 can cause a markedly more severe clinical phenotype than AR GRIN1-NDD caused by missense variants.

Reading comprehension difficulties in children with rolandic epilepsy.

AIM: Difficulties in reading comprehension can arise from either word reading or listening comprehension difficulties, or a combination of the two. We sought to determine whether children with rolandic epilepsy had poor reading comprehension relative to typically developing comparison children, and whether such difficulties were associated with word reading and/or general language comprehension difficulties. METHOD: In this cross-sectional study, children with rolandic epilepsy (n=25; 16 males, 9 females; mean age 9y 1mo, SD 1y 7mo) and a comparison group (n=39; 25 males, 14 females; mean age 9y 1mo, SD 1y 3mo) completed assessments of reading comprehension, listening comprehension, word/non-word reading, speech articulation, and Non-verbal IQ. RESULTS: Reading comprehension and word reading were worse in children with rolandic epilepsy (F1,61 =6.89, p=0.011, ηp2=0.10 and F1,61 =6.84, p=0.011, ηp2=0.10 respectively), with listening comprehension being marginal (F1,61 =3.81, p=0.055, ηp2=0.06). Word reading and listening comprehension made large and independent contributions to reading comprehension, explaining 70% of the variance. INTERPRETATION: Children with rolandic epilepsy may be at risk of reading comprehension difficulties. Thorough assessment of individual children is required to ascertain whether the difficulties lie with decoding text, or with general comprehension skills, or both. WHAT THIS PAPER ADDS: Children with rolandic epilepsy may be at risk of poor reading comprehension. This was related to poor word reading, poor listening comprehension, or both. Reading comprehension interventions should be tailored to the profile of difficulties.

Social cognition in children with epilepsy in mainstream education.

AIM: To establish whether deficits in social cognition are present in children with generalized or focal epilepsy in mainstream education, and whether any relation exists between social cognition, communication, and behaviour measures. METHOD: In a cross-sectional study, children with an epilepsy-only diagnoses in mainstream education (n=20 with generalized epilepsy; eight males, 12 females; mean age 11y 6mo, SD 2y 6mo; and n=27 with focal epilepsy; 12 males, 15 females; mean age 11y 8mo, SD 2y 2mo) and comparison participants (n=57; 28 males, 29 females; mean age 11y 2mo, SD 2y 4mo) were administered the Strange Stories task and the Mind in the Eyes task, as well as an IQ assessment. Parents completed the Children's Communication Checklist-2 and the Child Behavior Checklist (CBCL). RESULTS: Both groups of children with epilepsy performed more poorly than control children on the Mental Stories component of the Strange Stories task, F(2,101)=3.2, p<0.001. Performance on Mental Stories was related to pragmatic communication, but only in the generalized epilepsy group (r=0.51, p=0.03, 95% CI=0.2-0.8). There were no differences between epilepsy groups or control participants in the Mind in the Eyes task, F(2,101)=0.4, p=0.4. INTERPRETATION: Children with 'epilepsy only' are at risk of deficits in social cognition and may require appropriate support.

Clinical and radiological features of childhood cerebral infarction following varicella zoster virus infection.

The aim of the study was to describe the clinical and radiological features of childhood post-varicella cerebral infarction (PVCI). A retrospective review was undertaken of children with arterial ischaemic stroke (AIS) who had experienced varicella zoster virus (VZV) infection within the preceding year. Twenty-four children (15 males, nine females; age range at time of VZV infection 2mo-6y) were identified, with a median of 4 months between VZV and AIS (range 1wk-12mo). All had infarction in the middle cerebral artery (MCA) territory and abnormalities of the M1 segment; arteriopathy affected other arteries in 10 children. After a median of 27 months, six patients had recurrent transient ischaemic attacks (TIA), with new infarcts in two of 22 children on re-imaging. Arterial disease improved in 11 children, was stable in four, and progressed in seven (of whom four had recurrent TIA and two had re-infarction). PVCI affects young, previously healthy children within a few months of VZV infection and is characterized by MCA territory infarction and proximal MCA disease. One quarter of patients have recurrence, usually, but not inevitably, associated with progressive arteriopathy. Treatable co-existing AIS risk factors should always be excluded. A more comprehensive diagnostic evaluation should be considered in children with AIS who do not fit the clinical and radiological profile outlined, even where there is a history of recent VZV infection.