Implications of the KIWE trial for low-income and lower-middle-income countries
Authors: Jitendra Kumar Sahu, Priyanka Madaan, Jithangi Wanigasinghe, Pauline Samia, Aye Mya Min Aye, Esmatullah Hamed, Kanij Fatema, Kyaw Linn, Mimi L Mynak, Nicolás Garófalo Gómez, Prakash Poudel, Prem Chand, Samaahath Hassan
Journal: The Lancet Neurology (2024)

We read with interest the Article reporting findings of the KIWE trial,1Schoeler NE Marston L Lyons L et al.Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.Lancet Neurol. 2023; 22: 1113-1124Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar which compared the ketogenic diet with antiseizure medications in infants with drug-resistant epilepsy. The trial did not show a significant difference between diet and medication in terms of efficacy and tolerability; however, we wish to highlight several concerns. Given that 50% of the study cohort had infantile epileptic spasms syndrome (IESS), we trust that the findings are relevant to management practices of patients with IESS in low-income and lower-middle-income countries.2Sahu JK Madaan P Prakash K The landscape of infantile epileptic spasms syndrome in South Asia: peculiarities, challenges, and way forward.Lancet Reg Health Southeast Asia. 2023; 12100170 PubMed Google Scholar The trial found a low clinical response in infants on the ketogenic diet in terms of achieving seizure freedom at 8 weeks.1Schoeler NE Marston L Lyons L et al.Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trial.Lancet Neurol. 2023; 22: 1113-1124Summary Full Text Full Text PDF PubMed Scopus (5) Google Scholar However, in this era of precision medicine, characterisation of the electroclinical syndrome and the underlying cause or genetic diagnosis in the children who became seizure-free in both groups would be crucial for a better understanding of these findings.3Devi N Madaan P Kandoth N Bansal D Sahu JK Efficacy and safety of dietary therapies for childhood drug-resistant epilepsy: a systematic review and network meta-analysis.JAMA Pediatr. 2023; 177: 258-266Crossref PubMed Scopus (16) Google Scholar Electroclinical remission is a key aim in treating IESS, while a clinical response to either the ketogenic diet or antiseizure medications might be an over-representation of efficacy. The dose and choice of antiseizure medications in the comparison group were not specified, but they could have influenced outcomes. Antiseizure medications can have variable response rates (eg, 42% electroclinical response with nitrazepam) in patients with IESS, as shown in prospective studies.4Zahan S Sahu JK Madaan P et al.Effectiveness and safety of nitrazepam in children with resistant West syndrome.Indian J Pediatr. 2022; 89: 37-44Crossref PubMed Scopus (4) Google Scholar, 5Jain P Sahu JK Horn PS et al.Treatment of children with infantile spasms: a network meta-analysis.Dev Med Child Neurol. 2022; 64: 1330-1343Crossref PubMed Scopus (8) Google Scholar Although indirect comparison is not appropriate, these studies suggest that a trial comparing the ketogenic diet with other antiseizure medications might be enticing. A long treatment lag after diagnosis and a structural cause of the epilepsy, particularly in patients with IESS in low-income and lower-middle-income countries, can preclude a therapeutic response.2Sahu JK Madaan P Prakash K The landscape of infantile epileptic spasms syndrome in South Asia: peculiarities, challenges, and way forward.Lancet Reg Health Southeast Asia. 2023; 12100170 PubMed Google Scholar In the KIWE trial, the patients with IESS presumably had a short treatment lag akin to previous studies from the UK.5Jain P Sahu JK Horn PS et al.Treatment of children with infantile spasms: a network meta-analysis.Dev Med Child Neurol. 2022; 64: 1330-1343Crossref PubMed Scopus (8) Google Scholar The deaths of three children exclusively in the ketogenic diet group are of concern, as the study might not have been adequately powered for safety analyses. The authors did not perform a cost-effectiveness analysis for either group. The ketogenic diet often requires careful monitoring, consultations with dieticians, and laboratory testing to achieve optimum therapeutic response. Low-income and lower-middle-income countries are not only short of ketogenic diet centres but also paediatric neurologists. Therefore, a trial of other antiseizure medications might be a cost-effective alternative. Overall, we congratulate the KIWE trialists for their study, which provides crucial data on treatment options for infants with drug-resistant epilepsy. More data from future studies evaluating cause-specific IESS with a head-to-head comparison between various antiseizure medications and the ketogenic diet are needed. We declare no competing interests. Members of the South Asia allied IESS Research Group are listed in the appendix. Download .pdf (.06 MB) Help with pdf files Supplementary appendix Classic ketogenic diet versus further antiseizure medicine in infants with drug-resistant epilepsy (KIWE): a UK, multicentre, open-label, randomised clinical trialIn 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. Full-Text PDF Open Access