Developmental and epileptic encephalopathies

In the paper

“With >1000 genes now implicated as a monogenic cause of epilepsy in the Genes4Epilepsy database (http://github.com/bahlolab/genes4epilepsy)26 , the diverse functions of these genes highlight a vast array of biological processes that interact at cellular, organ and network levels.”

What the sources say

• Disputed

  The Results section reports 926 curated monogenic epilepsy genes, not more than 1000. It says 1128 genes were reviewed, but 202 were excluded for insufficient or disputed evidence; the larger figure therefore does not represent genes established as monogenic causes in this resource. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  cites [26] Oliver, K. L. et al. Genes4Epilepsy: an epilepsy gene resource. Epilepsia 64, 1368–1375 (2023). This study identified 926 known monogenic epilepsy genes in 2023 and showed that 825 genes were associated with DEEs; since publication, >1,000 genes have been listed on the publicly accessible database. sourceExperimental — accuracy not yet measured

In the paper

“A phase 2 RCT of soticlestat in patients with Dravet syndrome showed a significant placebo-adjusted median reduction in convulsive seizure frequency of 46% over the full treatment period, whereas reduction in drop seizures in those with LGS was not significant 188,191 .”

What the sources say

• Disputed

  Split into 2 atoms — 0 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Checked by a reasoning model — may be wrong.

  cites [188] Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376, 2011–2020 (2017). This is a key randomized controlled trial of cannabidiol in epilepsy showing that it is effective in Dravet syndrome, moving from anecdotal reports of the efficacy of cannabidiol to class I evidence for its use in DEE. sourceExperimental — accuracy not yet measured
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [191] Hahn, C. D. et al. A phase 2, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of soticlestat as adjunctive therapy in pediatric patients with Dravet syndrome or Lennox–Gastaut syndrome (ELEKTRA). Epilepsia 63, 2671–2683 (2022). source

In the paper

“DEEs typically present in childhood, before the age of 16 years, with a study from 2023 not identifying any presentations between 9 and 16 years 3 .”

What the sources say

• Supported

  The Cumulative Incidence section (p. e1366) reports that the oldest age of seizure onset in the DEE cohort was 9 years, and the study followed onset up to age 16. This supports the claim that the study found no presentations after age 9 and before age 16; it does not establish that DEEs cannot present later. (LLM, conf=0.90)

  cites [3] Poke, G., Stanley, J., Scheffer, I. E. & Sadleir, L. G. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023). This is the key epidemiology study of all DEEs with onset prior to 16 years of age, highlighting that DEEs have a cumulative incidence of 1 in 590 children and providing the cumulative incidence for several DEE syndromes. source

In the paper

“The DEEs are classified according to epilepsy syndrome, defined as a distinctive cluster of clinical and EEG features, often associated with aetiological findings 4 , however, not all patients can be classified with a known syndrome (Figure 2).”

What the sources say

• Supported

  Section 2.1 (“What is an epilepsy syndrome”; page not provided) defines an epilepsy syndrome as a characteristic cluster of clinical and EEG features, often supported by specific etiological findings. The paper also lists syndromes with DEE. The citation is attached to the definition, before the separate qualification about patients who cannot be classified with a known syndrome. (LLM, conf=0.94)

  cites [4] Wirrell, E. C. et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: report of the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1333–1348 (2022). source

In the paper

“In 2017, the ILAE expanded this concept to a 'developmental and epileptic encephalopathy', owing to a growing recognition that the aetiology, whether genetic, structural or otherwise, often causes developmental impairment in its own right 2 .”

What the sources say

• Partly supported

  The ‘Developmental and epileptic encephalopathies’ section (page unavailable) explicitly broadens the term because many severe genetic disorders cause developmental consequences independently of epileptic activity. It also mentions cortical malformations and acquired causes, but does not establish that structural or other aetiologies often cause developmental impairment in their own right. (LLM, conf=0.82)

  cites [2] Scheffer, I. E. et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 512–521 (2017). This is the first major revision of the International League Against Epilepsy Classification of the Epilepsies in almost three decades in which the term ‘developmental and epileptic encephalopathies’ was introduced and defined. sourceExperimental — accuracy not yet measured

In the paper

“DEEs are distinguished from epilepsies in adults and children with static intellectual disability, and epilepsies associated with progressive intellectual and neurological deterioration in which older patients of normal intellect develop cognitive, neurological or psychiatric impairment due to the underlying aetiology, which may be associated with an epileptic encephalopathy (for example, progress”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [11] Riney, K. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1443–1474 (2022). sourceExperimental — accuracy not yet measured

In the paper

“A DEE should be distinguished from a static developmental encephalopathy (typically resulting in intellectual disability) with epilepsy, in which the developmental encephalopathy alone (that is, not the epilepsy) causes developmental impairment 3 .”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [3] Poke, G., Stanley, J., Scheffer, I. E. & Sadleir, L. G. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023). This is the key epidemiology study of all DEEs with onset prior to 16 years of age, highlighting that DEEs have a cumulative incidence of 1 in 590 children and providing the cumulative incidence for several DEE syndromes. source

In the paper

“In 2022, LGS was defined by the ILAE for the first time, with the additional EEG feature of generalized paroxysmal fast activity in sleep 7 .”

What the sources say

• Partly supported

  Section 5.2 defines LGS and includes generalized paroxysmal fast activity among its EEG features; §5.2.5 says the pattern is often seen during sleep. The paper does not establish that this was the ILAE’s first definition of LGS or that the EEG feature was newly added. (LLM, conf=0.84)

  cites [7] Specchio, N. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1398–1442 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in childhood and includes DEEs. sourceExperimental — accuracy not yet measured

In the paper

“SUDEP rates for different genetic DEE syndromes have not been well defined, with the exception of Dravet syndrome, which has a Dravet-specific SUDEP rate of 4.4 in 1000 person-years (98% CI 2.3-7.8)19 , accounting for most of the Dravet-specific mortality.”

What the sources say

• Partly supported

  The Results report a Dravet-specific SUDEP rate of 4.4 per 1,000 person-years, but identify 2.3–7.8 as a 95% CI, not a 98% CI. Table 3 shows SUDEP accounted for 12 of 23 deaths (52%) in the Dravet group, supporting the mortality portion of the claim. (LLM, conf=0.91)

  cites [19] Donnan, A. M., Schneider, A. L., Russ-Hall, S., Churilov, L. & Scheffer, I. E. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology 100, e1712–e1722 (2023). This study examined the frequency of convulsive and non-convulsive status epilepticus and mortality rates in different genetic DEEs, informing counselling of families, diagnosis and clinical management. sourceExperimental — accuracy not yet measured

In the paper

“The most common DEE syndrome is Infantile Epileptic Spasms Syndrome (IESS) with an incidence of 30.7 in 100,000 individuals (95% CI 22.9-40.2) to 48.9 in 100,000 individuals (95% CI 37.0-64.7);~27% of IESS have a structural aetiology 3,9 .”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  cites [3] Poke, G., Stanley, J., Scheffer, I. E. & Sadleir, L. G. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023). This is the key epidemiology study of all DEEs with onset prior to 16 years of age, highlighting that DEEs have a cumulative incidence of 1 in 590 children and providing the cumulative incidence for several DEE syndromes. sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [9] Symonds, J. D. et al. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain 144, 2879–2891 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Seizure onset under age 3 months in SCN2A DEEs and 6 months in SCN8A DEEs, is associated with GOF 34,35 , and SCBs are efficacious in these phenotypes 34 .”

What the sources say

• Partly supported

  The Discussion (p. 13) associates SCN2A epilepsy onset before 3 months with gain-of-function mutations and a relatively good response to sodium-channel blockers. The treatment section (p. 17) cautions that this response is based on retrospective observations. Our copy does not establish the claimed 6-month threshold, gain-of-function association, or blocker efficacy for SCN8A DEEs (searched: SCN8A). (LLM, conf=0.90)

  cites [34] Wolff, M. et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140, 1316–1336 (2017). sourceExperimental — accuracy not yet measured
• Partly supported

  The phenotype-correlations discussion (p. 25) reports an approximately three-month GOF/LOF onset boundary for SCN2A, but describes overlapping onset ages for SCN8A rather than a six-month boundary. The treatment-effects results (p. 22) find better responses to sodium-channel blockers in SCN8A GOF carriers; they do not establish efficacy for SCN2A DEE in this paper. (LLM, conf=0.86)

  cites [35] Johannesen, K. M. et al. Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications. Brain 145, 2991–3009 (2022). sourceExperimental — accuracy not yet measured

In the paper

“The established mortality rate for Dravet syndrome is that 17% of patients die by age 20 years 20 .”

What the sources say

• Partly supported

  The ‘Patients who died before 18 years of age’ section reports that 6 of 37 patients (16.2%) died in childhood, all before age 13. This supports a mortality figure near 17% by age 20 for this cohort, but not an established rate for all patients with Dravet syndrome. The copy provides no page number for this passage. (LLM, conf=0.88)

  cites [20] Akiyama, M., Kobayashi, K., Yoshinaga, H. & Ohtsuka, Y. A long-term follow-up study of Dravet syndrome up to adulthood. Epilepsia 51, 1043–1052 (2010). sourceExperimental — accuracy not yet measured

In the paper

“other causes include cerebral oedema following status epilepticus 18 , chest infections and accidental causes 19 .”

What the sources say

• ?Not checked — no full text of the sourcecites [18] Myers, K. A. et al. Fatal cerebral edema with status epilepticus in children with Dravet syndrome: report of 5 cases. Pediatrics 139, e20161933 (2017). source
• Supported

  Citation 19 is attached to chest infections and accidental causes, not to cerebral oedema following status epilepticus, which has a separate citation. The Discussion (p. e1717) lists respiratory infection and drowning among causes of death in the genetic DEE cohort; Table 3 also records pneumonia and drowning. (LLM, conf=0.91)

  cites [19] Donnan, A. M., Schneider, A. L., Russ-Hall, S., Churilov, L. & Scheffer, I. E. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology 100, e1712–e1722 (2023). This study examined the frequency of convulsive and non-convulsive status epilepticus and mortality rates in different genetic DEEs, informing counselling of families, diagnosis and clinical management. source

In the paper

“Agespecific incidence varies through childhood with ~75% of cases beginning under 3 years of age, with a cumulative incidence estimated at 122 in 100,000 children (95% CI 102-146) in a retrospective study in Wellington 3 .”

What the sources say

• Supported

  The Cumulative Incidence section (p. e1366) reports that 51%, 13%, and 9% of DEE cases began in the first, second, and third years of life—73% before age 3, consistent with approximately 75%. Its table gives a cumulative incidence of 122 per 100,000 children (95% CI 102–146) for DEE with onset before age 3; the Methods identify the Wellington cohort. (LLM, conf=0.91)

  cites [3] Poke, G., Stanley, J., Scheffer, I. E. & Sadleir, L. G. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023). This is the key epidemiology study of all DEEs with onset prior to 16 years of age, highlighting that DEEs have a cumulative incidence of 1 in 590 children and providing the cumulative incidence for several DEE syndromes. source

In the paper

“SCN1A LOF particularly affects inhibitory interneurons, leading to impaired inhibition and epileptogenesis 29,30 , with early ataxia and later crouch gait in Dravet syndrome likely due to involvement of cerebellar Purkinje neurons 31 .”

What the sources say

• Supported

  The Introduction links SCN1A loss of function to Dravet syndrome and describes a disproportionate effect on inhibitory interneuron excitability. The Results report reduced firing in patient-derived inhibitory neurons, supporting the cited explanation for impaired inhibition and epilepsy. The Purkinje-neuron and gait clause carries a separate citation (31), so it is not attributed to this paper. (LLM, conf=0.88)

  cites [29] Sun, Y. et al. A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet syndrome patients. eLife 5, e13073 (2016). source
• Supported

  The citation to this paper is attached to the first clause about inhibitory interneurons and epilepsy, not the later clause about gait and Purkinje neurons. The Introduction reports dysfunction of GABAergic interneurons in Scn1a+/− mice and impaired transmission from parvalbumin interneurons to principal cells; it identifies that dysfunction as a mechanism of Dravet syndrome pathology, including epilepsy. (LLM, conf=0.90)

  cites [30] Kaneko, K. et al. Developmentally regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome. Cell Rep. 38, 110580 (2022). source
• ?Not checked — no full text of the sourcecites [31] Rodda, J. M., Scheffer, I. E., McMahon, J. M., Berkovic, S. F. & Graham, H. K. Progressive gait deterioration in adolescents with Dravet syndrome. Arch. Neurol. 69, 873–878 (2012). source

In the paper

“Taken together, genetic DEEs may cause structural changes, such as MCDs, reinforcing that a genetic aetiology should be sought for MCDs which are often associated with a DEE 40,41 .”

What the sources say

• Partly supported

  The Introduction’s “Genes, biological pathways, and mosaicism” section reports many genes associated with MCD, and the “Clinical features” section says dysplastic megalencephaly can include epileptic encephalopathies. These passages support seeking a genetic aetiology for MCD, but they do not establish that a genetic developmental and epileptic encephalopathy itself causes the structural malformation; they describe genetic causes of MCD alongside its clinical features. No page numbers were provided in our copy. (LLM, conf=0.84)

  cites [40] Guerrini, R. & Dobyns, W. B. Malformations of cortical development: clinical features and genetic causes. Lancet Neurol. 13, 710–726 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction identifies polymicrogyria as an MCD that commonly presents with epilepsy, and the Results identify genetic explanations in 90 of 275 affected families. The Discussion recommends genetic investigation, including ion-conduction genes, for people with polymicrogyria. The paper does not establish that genetic developmental and epileptic encephalopathies (DEEs) themselves cause MCDs, or extend its findings to MCDs generally. Page numbers are not available in our copy. (LLM, conf=0.84)

  cites [41] Akula, S. K. et al. Exome sequencing and the identification of new genes and shared mechanisms in polymicrogyria. JAMA Neurol. 80, 980–988 (2023). sourceExperimental — accuracy not yet measured

In the paper

“In comparison, the estimated incidence of all epilepsies presenting under 3 years was 239 in 100,000 (95% CI 216-263) in a prospective study in Scotland, UK, with DEEs accounting for 86.1 in 100,000 (95% CI 72.7-101.3)children 9 .”

What the sources say

• Supported

  The Results section on incidence reports an adjusted incidence of 239 per 100,000 live births (95% CI 216–263) for epilepsies presenting in the first 3 years of life in Scotland. Table 1 in Results > Classification gives the DEE incidence as 86.1 per 100,000 live births (95% CI 72.7–101.3). (LLM, conf=0.95)

  cites [9] Symonds, J. D. et al. Early childhood epilepsies: epidemiology, classification, aetiology, and socio-economic determinants. Brain 144, 2879–2891 (2021). source

In the paper

“LOF de novo KCNQ2 variants cause neonatal-onset EIDEE 42 , whereas inherited variants result in self-limited seizures 10 .”

What the sources say

• ?Not checked — no full text of the sourcecites [42] Weckhuysen, S. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15–25 (2012). source
• Supported

  Citation 10 is attached to the inherited-variant clause. The Genetics section describes autosomal dominant inheritance in families with self-limited neonatal epilepsy and identifies pathogenic KCNQ2 variants as its most common cause. It also notes that self-limited neonatal epilepsy can arise from de novo variants, so inheritance is not an exclusive distinction. (LLM, conf=0.89)

  cites [10] Zuberi, S. M. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1349–1397 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in the newborn and infantile periods and includes DEEs. source

In the paper

“IESS and LGS are defined by their seizure types and EEG features, and have multiple aetiologies, whereas Dravet syndrome is defined by electroclinical features, supported by a SCN1A pathogenic variant in 90% of cases 10,12 .”

What the sources say

• Partly supported

  The Dravet syndrome section says clinical diagnosis is supported by a pathogenic SCN1A variant, and the Genetics section says diagnosis requires typical clinical features rather than a variant alone. The stated frequency is over 80% (described as more than 80%–85% in Genetics), not the claimed 90%; no page number is available in our copy. (LLM, conf=0.88)

  cites [10] Zuberi, S. M. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1349–1397 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in the newborn and infantile periods and includes DEEs. sourceExperimental — accuracy not yet measured
• Supported

  The Discussion describes epilepsy syndromes in terms of seizure types, developmental course and EEG features, and examines those features in Dravet syndrome. It reports SCN1A pathogenic variants in 92% of its 228-patient Dravet cohort, consistent with the claim’s approximate 90%; the figure is specific to that cohort. (LLM, conf=0.88)

  cites [12] Li, W., Schneider, A. L. & Scheffer, I. E. Defining Dravet syndrome: an essential pre-requisite for precision medicine trials. Epilepsia 62, 2205–2217 (2021). source

In the paper

“Different genetic DEEs vary considerably in their SUDEP risk, which is increased in DEEs due to sodium channelopathies 19 .”

What the sources say

• Supported

  The Discussion (page not supplied) says genetic DEEs vary markedly in SUDEP rates. The Results (page not supplied) report SUDEP in three sodium-channel DEEs—SCN1A, SCN2A and SCN8A—and STXBP1, but none in the other genetic DEEs studied. This supports the claim without implying that SUDEP is exclusive to sodium channelopathies. (LLM, conf=0.93)

  cites [19] Donnan, A. M., Schneider, A. L., Russ-Hall, S., Churilov, L. & Scheffer, I. E. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology 100, e1712–e1722 (2023). This study examined the frequency of convulsive and non-convulsive status epilepticus and mortality rates in different genetic DEEs, informing counselling of families, diagnosis and clinical management. source

In the paper

“In Wellington, New Zealand, the cumulative incidence of DEEs with onset up to age 16 years has been estimated at 169 in 100,000 (95% CI 144-199) or 1 in 590 children, based on EEG ascertainment 3 .”

What the sources say

• Supported

  The Abstract reports a cumulative DEE incidence of 169 per 100,000 children (95% CI 144–199) in the Wellington region, with children ascertained using EEG records. The Statistical Analysis section defines cumulative incidence through age 16, and the Discussion gives the equivalent figure of 1 in 590 children. (LLM, conf=0.94)

  cites [3] Poke, G., Stanley, J., Scheffer, I. E. & Sadleir, L. G. Epidemiology of developmental and epileptic encephalopathy and of intellectual disability and epilepsy in children. Neurology 100, e1363–e1375 (2023). This is the key epidemiology study of all DEEs with onset prior to 16 years of age, highlighting that DEEs have a cumulative incidence of 1 in 590 children and providing the cumulative incidence for several DEE syndromes. source

In the paper

“Loss-of-function (LOF) missense or truncating variants cause Dravet syndrome, the prototypic DEE 13,27 , and also the non-DEE syndrome of Genetic Epilepsy with Febrile Seizures Plus (GEFS+) 28 .”

What the sources say

• Partly supported

  The Results (Gene-associated phenotypes; page not available) report SCN1A variants in 11 patients with Dravet syndrome and one with GEFS+, supporting the link between SCN1A and both syndromes. The paper identifies missense and predicted truncating variants but does not establish that the GEFS+ variant was loss-of-function or that loss-of-function variants cause both syndromes; it reports no genotype–phenotype association in this cohort. (LLM, conf=0.87)

  cites [13] Symonds, J. D. et al. Incidence and phenotypes of childhood-onset genetic epilepsies: a prospective population-based national cohort. Brain 142, 2303–2318 (2019). This Scottish epidemiological study provides the incidence and phenotypes of seizure disorders with onset under 3 years of age. sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [27] Dravet C. et al. in Epileptic Syndromes in Infancy, Childhood and Adolescence 6th edn (eds Bureau, M. et al.) 139–171 (Libbey Eurotext, 2019).
• ?Not checked — no full text of the sourcecites [28] Zhang, Y. H. et al. Genetic epilepsy with febrile seizures plus: refining the spectrum. Neurology 89, 1210–1219 (2017). source

In the paper

“KCNQ2 EIDEE typically causes severe to profound impairment, despite seizures remitting in early life in >50% of patients 10,42 .”

What the sources say

• Partly supported

  The KCNQ2-DEE Clinical context section says that over half of patients become seizure-free, but the timing ranges from a few months of age to several years, not necessarily early life. It describes developmental outcome as typically moderately to severely impaired; Table 9 gives a range from moderate to profound impairment. Neither establishes that impairment is typically severe to profound. (LLM, conf=0.88)

  cites [10] Zuberi, S. M. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1349–1397 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in the newborn and infantile periods and includes DEEs. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [42] Weckhuysen, S. et al. KCNQ2 encephalopathy: emerging phenotype of a neonatal epileptic encephalopathy. Ann. Neurol. 71, 15–25 (2012). source

In the paper

“DEPDC5 pathogenic variants were first reported in familial focal epilepsies 127,128 , and later associated with DEEs 129 .”

What the sources say

• ?Not checked — no full text of the sourcecites [127] Dibbens, L. M. et al. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat. Genet. 45, 546–551 (2013). source
• Supported

  The cited paper reports identifying DEPDC5 mutations in families with focal epilepsies, including familial focal epilepsy with variable foci (Abstract). This source is cited for the first clause; the later association with DEEs is assigned to citation 129, not to this paper. (LLM, conf=0.92)

  cites [128] Ishida, S. et al. Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat. Genet. 45, 552–555 (2013). source
• Supported

  The citation to this paper is attached to the later association with DEEs, not the earlier reports of familial focal epilepsy. In Results (page not provided), the paper identifies likely pathogenic DEPDC5 variants in patients with epileptic spasms; it describes the cohort as including West syndrome and other epileptic encephalopathies. The Discussion (page not provided) says these findings expand the DEPDC5 spectrum to more severe epilepsies presenting with spasms. (LLM, conf=0.87)

  cites [129] Carvill, G. L. et al. Epileptic spasms are a feature of DEPDC5 mTORopathy. Neurol. Genet. 1, e17 (2015). source

In the paper

“It is followed by rapid progression to a progressive myoclonus epilepsy, severe regression, visual failure and early death.”

What the sources say

• Partly supported

  The Introduction describes seizures, loss of language and psychomotor function, blindness, and premature death; the Discussion reports rapid functional decline. However, the Discussion says seizure types are highly variable and that myoclonic seizures *can* predominate as the disease progresses, rather than establishing progressive myoclonus epilepsy as the course for all patients. Page numbers were not available in our copy. (LLM, conf=0.86)

  cites [147] Nickel, M. et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child. Adolesc. Health 2, 582–590 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Heterozygous dominant negative GPHN variants cause DEEs 115 and biallelic LOF variants with EIMFS 116 , confirming the role of gephyrin in maintaining inhibitory signalling in the brain.”

What the sources say

• Partly supported

  The Results and Discussion report one patient with infantile-onset epileptic encephalopathy and a heterozygous GPHN-G375D variant that acts dominant-negatively and impairs inhibitory signalling. The Discussion suggests that this mutation leads to seizures, but one case does not establish the broader, unqualified claim that heterozygous dominant-negative GPHN variants cause DEEs. The biallelic-variant clause has a separate citation and is not attributed to this paper. (LLM, conf=0.84)

  cites [115] Dejanovic, B. et al. Simultaneous impairment of neuronal and metabolic function of mutated gephyrin in a patient with epileptic encephalopathy. EMBO Mol. Med. 7, 1580–1594 (2015). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [116] Macha, A. et al. Biallelic gephyrin variants lead to impaired GABAergic inhibition in a patient with developmental and epileptic encephalopathy. Hum. Mol. Genet. 31, 901–913 (2022). source

In the paper

“IQSEC2 is associated with DEEs; males are more severely affected than females with de novo pathogenic variants 64,111,112 .”

What the sources say

• Partly supported

  The Abstract lists IQSEC2 among genes with de novo mutations in patients with epileptic encephalopathies, supporting its connection to DEEs. Our copy does not report that males with de novo pathogenic IQSEC2 variants are more severely affected than females. (LLM, conf=0.88)

  cites [64] Epi4K Consortium & Epilepsy Phenome/Genome Project De novo mutations in epileptic encephalopathies. Nature 501, 217–221 (2013). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [111] Zerem, A. et al. The molecular and phenotypic spectrum of IQSEC2-related epilepsy. Epilepsia 57, 1858–1869 (2016). source
• ?Not checked — no full text of the sourcecites [112] Shoubridge, C., Harvey, R. J. & Dudding-Byth, T. IQSEC2 mutation update and review of the female-specific phenotype spectrum including intellectual disability and epilepsy. Hum. Mutat. 40, 5–24 (2019). source

In the paper

“GOF and LOF GABRB3 variants cause distinct DEE phenotypes with seizure onset under 6 months in GOF and after one year in LOF groups 73 .”

What the sources say

• Partly supported

  The Discussion describes distinct phenotypes, with GOF seizure onset typically at 1–3 months and LOF onset typically after one year. But the Results report a median LOF onset of 10.5 months, and the Discussion’s clinical flowchart uses six months or older as a LOF indicator. The claim overstates ‘after one year’ as applying to the LOF group generally. (LLM, conf=0.88)

  cites [73] Absalom, N. L. et al. Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies. Nat. Commun. 13, 1822 (2022). sourceExperimental — accuracy not yet measured

In the paper

“CLN2 disease causes the recessive neurodegenerative late-infantile form of neuronal ceroid lipofuscinosis, or late-infantile Batten disease 147 .”

What the sources say

• Partly supported

  The Introduction identifies CLN2 disease as a late-infantile form of neuronal ceroid lipofuscinosis and describes it as autosomal recessive and neurodegenerative. It does not say CLN2 disease causes that form; it says mutations in the CLN2 gene cause CLN2 disease. Our copy also does not establish the name “late-infantile Batten disease.” (LLM, conf=0.85)

  cites [147] Nickel, M. et al. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. Lancet Child. Adolesc. Health 2, 582–590 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Key genes include MECP2, a ubiquitously expressed methyl-CpG binding protein, for which LOF leads to Rett syndrome in girls and duplication typically leads to DEE with profound impairment in boys 136 .”

What the sources say

• Partly supported

  The Introduction (page not provided) associates MECP2 loss of function with Rett syndrome and says MECP2 duplication causes a distinct disorder primarily affecting males. The Abstract’s Objective classifies MECP2 Duplication Disorder as a developmental encephalopathy, but the paper does not establish that it typically causes profound impairment; its Abstract Results report the lowest severity scores for that group among the four disorders compared. (LLM, conf=0.87)

  cites [136] Cutri-French, C. et al. Comparison of core features in four developmental encephalopathies in the Rett natural history study. Ann. Neurol. 88, 396–406 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Heterozygous LOF variants in SLC2A1 encoding GLUT1, the major glucose transporter at the blood-brain barrier, cause early onset absence epilepsy, ataxia, epilepsy with myoclonic-atonic seizures, and exercise-induced dyskinesia 93 .”

What the sources say

• Supported

  The introduction links SLC2A1 mutations to early-onset absence epilepsy and describes families with exertional dyskinesia. The Results and patient table identify SLC2A1 variants in patients with myoclonic-atonic seizures, ataxia and exercise-triggered dyskinesia; the Comment reports reduced glucose transport from the studied variants. The introduction also identifies GLUT1 as the main glucose transporter across the blood–brain barrier. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [93] Mullen, S. A. et al. Glucose transporter 1 deficiency as a treatable cause of myoclonic astatic epilepsy. Arch. Neurol. 68, 1152–1155 (2011). source

In the paper

“Studies employing deep targeted sequencing in resected brain tissue highlight the role of brainrestricted somatic mosaic variants in nearly all of these genes in FCD type II, sometimes with hemimegalencephaly 123 , with variant allele frequencies as low as 0.01% 130 .”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [123] Iffland, P. H. II, Carson, V., Bordey, A. & Crino, P. B. GATORopathies: the role of amino acid regulatory gene mutations in epilepsy and cortical malformations. Epilepsia 60, 2163–2173 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [130] Pirozzi, F. et al. Profiling PI3K-AKT-MTOR variants in focal brain malformations reveals new insights for diagnostic care. Brain 145, 925–938 (2022). sourceExperimental — accuracy not yet measured

In the paper

“Overall, relatively few patients with DEEs are candidates for epilepsy surgery but, if a unifocal resectable lesion is identified, such as a FCD, successful surgery can be transformational 166,171 .”

What the sources say

• Partly supported

  The Discussion reports that FCD occurred in 12% of infants with severe epilepsies of infancy and that surgery may control seizures, potentially enabling developmental acceleration. It does not establish how many patients with DEEs are surgical candidates or report surgical outcomes; its population is also narrower than DEEs generally. (LLM, conf=0.85)

  cites [166] Howell, K. B. et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 59, 1177–1187 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results identify focal cortical dysplasia (FCD) as a common etiology in the surgical studies, and the Discussion reports seizure freedom in 68.8% of carefully selected children with epileptic spasms after resective surgery. The paper does not establish that relatively few patients with DEEs are surgical candidates, and its outcomes are specific to children with epileptic spasms rather than DEEs generally. Page numbers were not available in our copy. (LLM, conf=0.87)

  cites [171] Kolosky, T. et al. Epilepsy surgery for children with epileptic spasms: a systematic review and meta-analysis with focus on predictors and outcomes. Epilepsia Open. 9, 1136–1147 (2024). sourceExperimental — accuracy not yet measured

In the paper

“From diagnosis, families experience considerable grief and need intense support as the disease evolves 160,161 .”

What the sources say

• ?Not checked — no full text of the sourcecites [160] Brett, G. R. et al. Parental experiences of ultrarapid genomic testing for their critically unwell infants and children. Genet. Med. 22, 1976–1985 (2020). source
• Partly supported

  The Discussion (page not available) says rapid genomic testing requires appropriate counseling in emotionally charged, rapidly evolving clinical situations, and Participant Demographics reports that genetic counselors saw 88% of families. These passages support a need for counseling around diagnosis, but they do not establish that families experience considerable grief from diagnosis or need intense support as the disease evolves. (LLM, conf=0.76)

  cites [161] Australian Genomics Health Alliance Acute Care Flagship et al. Feasibility of ultra-rapid exome sequencing in critically Ill infants and children with suspected monogenic conditions in the australian public health care system. JAMA 323, 2503–2511 (2020). sourceExperimental — accuracy not yet measured

In the paper

“As one-third of patients present with febrile status epilepticus, either a hemiclonic or generalized tonicclonic seizure, the diagnosis of Dravet syndrome may be considered from age 6 months when development and the EEG are typically normal 12,158 .”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [12] Li, W., Schneider, A. L. & Scheffer, I. E. Defining Dravet syndrome: an essential pre-requisite for precision medicine trials. Epilepsia 62, 2205–2217 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (p. 1) describes early seizures as often prolonged and fever-associated, with normal early development. The Phenotype section (p. 3) reports onset at 2–6 months in seven patients. Our copy does not establish that one-third present with febrile status epilepticus, describe hemiclonic presentation or normal early EEG findings, or give a diagnostic recommendation from age 6 months. (LLM, conf=0.88)

  cites [158] Claes, L. et al. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am. J. Hum. Genet. 68, 1327–1332 (2001). sourceExperimental — accuracy not yet measured

In the paper

“SCN1A again provides a good example with Dravet syndrome arising due to LOF pathogenic variants 169 , and GOF pathogenic variants causing a profound Early Infantile DEE with an expanded phenotypic spectrum 32,33 .”

What the sources say

• Supported

  The “Early Onset SCN1A DEE” section explicitly contrasts loss of SCN1A function in Dravet syndrome with gain of function in early-onset SCN1A DEE. It describes the latter as a profound syndrome involving an increasingly recognized range of pathogenic variants. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [169] Scheffer, I. E. & Nabbout, R. SCN1A-related phenotypes: epilepsy and beyond. Epilepsia 60, S17–S24 (2019). source
• Partly supported

  The Discussion describes a distinct, profound early-infantile SCN1A developmental and epileptic encephalopathy, supporting the expanded-phenotype part of the claim. But it presents gain of function as speculation and says functional studies are needed to establish the mechanism. The Dravet loss-of-function statement is attached to a different citation. (LLM, conf=0.89)

  cites [32] Sadleir, L. G. et al. Not all SCN1A epileptic encephalopathies are Dravet syndrome: early profound Thr226Met phenotype. Neurology 89, 1035–1042 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The Discussion section, “SCN1A related GOF epilepsies—a phenotypic spectrum,” states that SCN1A gain-of-function disease includes severe neonatal and early infantile developmental and epileptic encephalopathies across a spectrum of phenotypes. The Introduction describes profound developmental impairment in early infantile DEE; the paper also contrasts these GOF phenotypes with LOF-associated Dravet syndrome. (LLM, conf=0.94)

  cites [33] Brunklaus, A. et al. The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications. Brain 145, 3816–3831 (2022). This study expands the spectrum of SCN1A DEEs associated with GOF pathogenic variants, highlighting the therapeutic implications for the GOF SCN1A diseases. source

In the paper

“DEEs include a wide range of epilepsy syndromes, defined by their electroclinical features and, in some cases, imaging findings (Figure 2) 4, 7, 10, 11, 162 .”

What the sources say

• Supported

  Section 2.1 defines epilepsy syndromes by characteristic clinical and EEG features and identifies DEE as a group of syndromes. Section 3.1 names several DEE syndromes, while the Discussion says syndrome descriptions include electroclinical features and, where relevant, imaging results. Page numbers are not available in our copy. (LLM, conf=0.89)

  cites [4] Wirrell, E. C. et al. Methodology for classification and definition of epilepsy syndromes with list of syndromes: report of the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1333–1348 (2022). source
• Supported

  Section 5 describes several childhood developmental and epileptic encephalopathy (DEE) syndromes, while the Discussion says syndrome diagnosis requires an electroclinical approach. Sections 5.4.6 and 5.5.6 describe imaging findings for particular syndromes, supporting the qualification that imaging findings are relevant in some cases. (LLM, conf=0.90)

  cites [7] Specchio, N. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1398–1442 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in childhood and includes DEEs. source
• Supported

  The Etiology-specific syndromes section describes multiple DEEs with distinct clinical and EEG phenotypes and, where relevant, neuroimaging correlates. The paper addresses syndromes with onset in neonates and infants; within that scope, it supports the claim. (LLM, conf=0.89)

  cites [10] Zuberi, S. M. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1349–1397 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in the newborn and infantile periods and includes DEEs. source
• Partly supported

  The Discussion says syndrome diagnosis relies predominantly on electroclinical presentation, and §2.4.2 describes Rasmussen syndrome diagnosis as based on clinical presentation and imaging findings. Section 2.6 identifies syndromes that can be DEEs, but this paper addresses only a small, rare group with variable age at onset; it does not establish the claim’s broader characterization of DEEs as including a wide range of syndromes. (LLM, conf=0.82)

  cites [11] Riney, K. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1443–1474 (2022). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction and §1.4 (Electroencephalogram; page unavailable) define idiopathic generalized epilepsy syndromes and mention DEEs only in passing. The imaging sections address those idiopathic generalized syndromes, not how DEEs are defined. Searches for DEEs and electroclinical or imaging-based definitions found no passage supporting the attributed claim. (LLM, conf=0.76)

  cites [162] Hirsch, E. et al. ILAE definition of the idiopathic generalized epilepsy syndromes: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1475–1499 (2022). sourceExperimental — accuracy not yet measured

In the paper

“Genetic DEEs are most commonly regarded as de novo dominant disorders; however, more DEE genes follow autosomal recessive than dominant inheritance, with a small number following X-linked or mitochondrial inheritance patterns 26 .”

What the sources say

• Supported

  The Results (Monogenic epilepsy genes and insights; page unavailable) say that de novo dominant DEE genes led the initial surge in discoveries, while DEE genes in the curated resource are predominantly autosomal recessive. The same section says X-linked and mitochondrial genes form a small portion of the resource overall. This is a claim about numbers of genes, not numbers of affected patients—a distinction the paper explicitly makes. (LLM, conf=0.86)

  cites [26] Oliver, K. L. et al. Genes4Epilepsy: an epilepsy gene resource. Epilepsia 64, 1368–1375 (2023). This study identified 926 known monogenic epilepsy genes in 2023 and showed that 825 genes were associated with DEEs; since publication, >1,000 genes have been listed on the publicly accessible database. source

In the paper

“For specific DEE syndromes, appropriate management may facilitate a good outcome with the child ultimately being of normal intellect, as is common in the epileptic encephalopathy of Epilepsy with Myoclonic-Atonic Seizures 7, 150 .”

What the sources say

• Partly supported

  Section 5.1 says two thirds of children with epilepsy with myoclonic-atonic seizures have normal development before onset and that developmental stagnation or regression improves once seizures are controlled. Section 5.1.3 reports remission in two thirds and says development may return to premorbid levels, supporting the possibility of a good outcome. It also says some children have intellectual disability; it does not establish that normal intellect at outcome is common or that appropriate management ensures it. (LLM, conf=0.84)

  cites [7] Specchio, N. et al. International League Against Epilepsy classification and definition of epilepsy syndromes with onset in childhood: position paper by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1398–1442 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in childhood and includes DEEs. sourceExperimental — accuracy not yet measured
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [150] Guerrini R. et al. in Epileptic Syndromes in Infancy, Childhood and Adolesence 6th edn (eds Bureau, M. et al.) 173–188 (Libbey Eurotext, 2019).

In the paper

“Indeed, a recent study of rapid genome sequencing (median time from seizure onset to sequencing result of 37 days) in infants with seizures beginning under one year of age, identified the genetic aetiology in 46% of 100 children, with clinical utility in 56%, prognostic counselling in 86% and genetic counselling implications in all those with a pathogenic variant 157 .”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [157] D’Gama, A. M. et al. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. Lancet Neurol. 22, 812–825 (2023). This international collaborative study analysed the yield of rapid genome sequencing in infants presenting with seizures in the first year of life and highlighted the utility in determining management, prognostic and reproductive counselling. sourceExperimental — accuracy not yet measured

In the paper

“Epilepsy syndromes are defined by their age of onset, seizure types 163 , EEG features, developmental course, and associated features.”

What the sources say

• Supported

  The citation appears immediately after “seizure types,” so it is assessed for that part of the sentence. The paper states that seizure types are a key component of the broader classification of epilepsies and that grouping them can link to specific syndromes (section R; Corresponding author section, page unavailable). It does not establish the other listed features, which are not the part cited here. (LLM, conf=0.84)

  cites [163] Fisher, R. S. et al. Operational classification of seizure types by the International League Against Epilepsy: position paper of the ILAE Commission for Classification and Terminology. Epilepsia 58, 522–530 (2017). source

In the paper

“The aetiology of DEEs is frequently genetic, and may be associated with normal imaging, diffuse or focal structural abnormalities such as MCD 164,165 and, less commonly, metabolic features.”

What the sources say

• Supported

  The citation is attached to the structural-abnormality example, not the subsequent statement about metabolic features. The Results describe focal cortical dysplasia in a patient with an STXBP1 mutation, while the Discussion reports variable MRI findings in STXBP1-related epilepsy, including a previously reported patient with a normal MRI but dysplasia found at surgery. The copy provides no page numbers. (LLM, conf=0.88)

  cites [164] Uddin, M. et al. Germline and somatic mutations in STXBP1 with diverse neurodevelopmental phenotypes. Neurol. Genet. 3, e199 (2017). source
• Supported

  The citation is attached to the example of malformations of cortical development (MCD). The Introduction describes a child with genetically related DEE, and the Histology section reports focal cortical dysplasia and mild MCD in that child. Page numbers are not available in our copy. (LLM, conf=0.90)

  cites [165] Nagarajan, L. et al. Epilepsy surgery in PCDH 19 related developmental and epileptic encephalopathy: a case report. Epilepsy Behav. Rep. 19, 100560 (2022). source

In the paper

“The genes that cause EIMFS may follow autosomal dominant, X-linked and autosomal recessive inheritance, so an understanding of how each gene is inherited is essential when providing accurate diagnostic and genetic counselling for families 168 .”

What the sources say

• Supported

  The Discussion’s “Novel genetic causes of EIMFS” section identifies dominant, X-linked, and recessive EIMFS genes. The “Inheritance and genetic counseling” section explains that inheritance patterns have implications for accurate reproductive counseling. Page numbers were not supplied in our copy. (LLM, conf=0.94)

  cites [168] Burgess, R. et al. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann. Neurol. 86, 821–831 (2019). source

In the paper

“whereas EIMFS is highly genetically heterogeneous with >30 genes implicated and 70% of all cases having a pathogenic variant of major effect identified.”

What the sources say

• ?Could not verify

  The Results discuss genes associated with developmental and epileptic encephalopathies generally, and the Discussion reports a genetic diagnosis in more than 50% of patients with a DEE. Neither passage gives an EIMFS-specific gene count or a 70% diagnostic rate. Searches for EIMFS, migrating focal seizures, and the claimed figures found no passage addressing those specifics. (LLM, conf=0.75)

  cites [26] Oliver, K. L. et al. Genes4Epilepsy: an epilepsy gene resource. Epilepsia 64, 1368–1375 (2023). This study identified 926 known monogenic epilepsy genes in 2023 and showed that 825 genes were associated with DEEs; since publication, >1,000 genes have been listed on the publicly accessible database. sourceExperimental — accuracy not yet measured

In the paper

“For example, mutations in the sodium channel subunit genes, SCN1A, SCN2A and SCN8A, cause DEEs and self-limited epilepsies, which require very different treatment approaches 10 .”

What the sources say

• Partly supported

  The Genetics passages (page unavailable) link SCN1A to Dravet syndrome and early infantile encephalopathy, SCN2A to both self-limited epilepsy and DEE, and SCN8A to DEE. The Differential diagnosis and Dravet syndrome diagnostic-criteria passages indicate that treatment response can differ, but our copy does not establish a self-limited epilepsy associated with SCN8A or distinct treatment approaches for all three genes. (LLM, conf=0.84)

  cites [10] Zuberi, S. M. et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia 63, 1349–1397 (2022). This is one of four papers officially defining epilepsy syndromes for the International League Against Epilepsy and focuses on syndromes beginning in the newborn and infantile periods and includes DEEs. sourceExperimental — accuracy not yet measured

In the paper

“MCD, including FCD, may be associated with a pathogenic germline or somatic variant, which may show a mutation gradient in resected brain tissue.”

What the sources say

• Supported

  The Results and Discussion report germline and somatic DEPDC5 variants in a patient with FCD, identified in resected brain tissue. They also report a higher somatic mutation rate in the seizure-onset zone than in the surrounding epileptogenic zone. This supports the claim's qualified statement about MCD, including FCD. (LLM, conf=0.92)

  cites [124] Ribierre, T. et al. Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. J. Clin. Invest. 128, 2452–2458 (2018). source

In the paper

“Cognitive decline may indicate the need for sleep EEG studies to identify a, so far, unrecognised epileptic encephalopathy, such as DEE-SWAS or EE-SWAS 170 .”

What the sources say

• Supported

  The Introduction (page unavailable) identifies cognitive regression as a feature of DEE-SWAS and EE-SWAS and describes their distinctive EEG activity during non-REM sleep. The Discussion (page unavailable) notes that EEG testing was sometimes delayed, particularly in children without seizures. Together, these passages support the cautious suggestion that cognitive decline may warrant a sleep EEG to identify an unrecognised syndrome. (LLM, conf=0.86)

  cites [170] Viswanathan, S. et al. Solving the etiology of developmental and epileptic encephalopathy with spike-wave activation in Sleep (D/EE-SWAS). Ann Neurol. https://doi.org/10.1002/ana.27041 (2024). source

In the paper

“By contrast, a 2023 genome sequencing study of infants presenting with seizures under age 1 year identified the causal variant in 43% with immediate treatment implications in 56%, informing additional evaluation in 65% and prognostic counselling in 86% 157 .”

What the sources say

• Supported

  The Results report genetic diagnoses in 43 of 100 infants with new-onset epilepsy. Among the 43 diagnosed infants, diagnoses influenced treatment in 56%, led to additional evaluation in 65%, and informed prognosis in 86%. Those three percentages use the diagnosed group, not all 100 infants, as their denominator. (LLM, conf=0.90)

  cites [157] D’Gama, A. M. et al. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. Lancet Neurol. 22, 812–825 (2023). This international collaborative study analysed the yield of rapid genome sequencing in infants presenting with seizures in the first year of life and highlighted the utility in determining management, prognostic and reproductive counselling. source

In the paper

“Routine genetic testing often begins with a chromosomal microarray as causative copy number variants (CNVs) are identified in at least 4% of patients with DEEs 172 .”

What the sources say

• Partly supported

  The Discussion reports clearly pathogenic CNVs in 4.1% of 315 patients with epileptic encephalopathies and suggests considering array CGH in their genetic evaluation. It does not establish that routine genetic testing often begins with a chromosomal microarray. (LLM, conf=0.88)

  cites [172] Mefford, H. C. et al. Rare copy number variants are an important cause of epileptic encephalopathies. Ann. Neurol. 70, 974–985 (2011). sourceExperimental — accuracy not yet measured

In the paper

“Specifically, a genetic or presumed genetic basis was identified in 62 (54%) patients: 14 with FCD, 17 had other brain malformations, 6 had a metabolic disorder, 9 with chromosomal disorders and 16 had a single gene disorder, and 14 with acquired brain lesions 8, 166 .”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Howell, K. B. et al. The severe epilepsy syndromes of infancy: a population-based study. Epilepsia 62, 358–370 (2021). source
• Partly supported

  The Results > Etiology section reports 62 infants (54%) with genetic or presumed genetic etiologies and gives the stated counts for FCD, other brain malformations, metabolic disorders, chromosomal abnormalities, and single-gene disorders. It separately classifies 14 infants as having acquired brain injury; they are not part of the 62 with genetic or presumed genetic etiologies. (LLM, conf=0.92)

  cites [166] Howell, K. B. et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 59, 1177–1187 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Parental mosaicism places parents at an increased risk of having a second child with a DEE, as a small population of their sperm or ova carry the pathogenic variant.”

What the sources say

• Partly supported

  The TO THE EDITOR section links parental mosaicism to recurrence risk and reports affected siblings who shared a proband’s mutation. It says the authors tested blood or saliva to infer gonadal mosaicism, not sperm or ova. The claim’s explanation that a small population of gametes carries the variant is therefore more definite than the paper’s evidence. (LLM, conf=0.86)

  cites [175] Myers, C. T. et al. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378, 1646–1648 (2018). This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications. sourceExperimental — accuracy not yet measured

In the paper

“Mosaic pathogenic CNVs are increasingly identified, with a greater yield from salivary DNA than from blood-derived DNA, as salivary epithelial cells are embryologically closer to neural cells, deriving from ectoderm, compared with lymphocytes 173 .”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [173] Francis, D. I. et al. Comparing saliva and blood for the detection of mosaic genomic abnormalities that cause syndromic intellectual disability. Eur. J. Hum. Genet. 31, 521–525 (2022). sourceExperimental — accuracy not yet measured

In the paper

“Randomised placebo-controlled trials (RCTs) of cannabidiol demonstrated efficacy in Dravet syndrome, LGS and TSC, with significant median percent reductions in target seizures compared with placebo of 38.9% 188 , 41.9% 189 and 48.6% 190 .”

What the sources say

• Supported

  The Seizure Frequency section reports a 38.9% median reduction from baseline in convulsive-seizure frequency with cannabidiol in Dravet syndrome, versus 13.3% with placebo; the adjusted between-group difference was significant (P = 0.01). Citation 188 is attached to the Dravet result, not the separately cited LGS and TSC results. (LLM, conf=0.93)

  cites [188] Devinsky, O. et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N. Engl. J. Med. 376, 2011–2020 (2017). This is a key randomized controlled trial of cannabidiol in epilepsy showing that it is effective in Dravet syndrome, moving from anecdotal reports of the efficacy of cannabidiol to class I evidence for its use in DEE. source
• Supported

  The citation to this paper is attached to the LGS result, not the Dravet syndrome or TSC figures. The RESULTS section (page not provided) reports a 41.9% median reduction from baseline in drop-seizure frequency with 20 mg/kg/day cannabidiol, versus 17.2% with placebo (P=0.005). The 41.9% is the treatment group's reduction, not the percentage-point difference from placebo. (LLM, conf=0.94)

  cites [189] Devinsky, O. et al. Effect of cannabidiol on drop seizures in the Lennox–Gastaut syndrome. N. Engl. J. Med. 378, 1888–1897 (2018). source
• Partly supported

  The Results > Primary Outcome section reports a 48.6% reduction from baseline in target seizures for the 25 mg/kg/day cannabidiol group, versus 26.5% for placebo, supporting efficacy in TSC. But 48.6% is not the reduction relative to placebo, which the paper reports as 30.1%; the reported median reduction in a sensitivity analysis is 43.4%, not 48.6%. (LLM, conf=0.88)

  cites [190] Thiele, E. A. et al. Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex: a placebo-controlled randomized clinical trial. JAMA Neurol. 78, 285–292 (2021). sourceExperimental — accuracy not yet measured

In the paper

“Trials targeting specific channelopathies are being developed: potent selective potassium channel openers, retigabine and ezogabine, for KCNQ2-DEE; a powerful, highly selective Nav1.6 inhibitor for SCN8A-DEE 186 , and a selective GluN2B negative allosteric modulator, radiprodil, for GRIN2B GOF DEE 187 .”

What the sources say

• ?Not checked — no full text of the sourcecites [186] Bialer, M. et al. Progress report on new antiepileptic drugs: a summary of the Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI): I. Drugs in preclinical and early clinical development. Epilepsia 63, 2865–2882 (2022). source
• Partly supported

  Split into 3 atoms — 0 confirmed, 3 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [187] Mullier, B. et al. GRIN2B gain of function mutations are sensitive to radiprodil, a negative allosteric modulator of GluN2B-containing NMDA receptors. Neuropharmacology 123, 322–331 (2017). sourceExperimental — accuracy not yet measured

In the paper

“In a 2021 observational study in 293 patients with genetic epilepsies, treatment changes were undertaken because of the genetic findings in 32%, including rational precision medicine treatment or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms 183 .”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [183] Balestrini, S. et al. Real-life survey of pitfalls and successes of precision medicine in genetic epilepsies. J. Neurol. Neurosurg. Psychiatry 92, 1044–1052 (2021). source

In the paper

“As genomic DEE episignatures are identified, testing may clarify the pathogenicity of variants of unknown significance and identify other pathogenic variants with imprinting and repeat expansion disorders 142, 179 .”

What the sources say

• Partly supported

  The Introduction and Results section on episignature screening say that episignatures can help resolve variants of uncertain significance; the Results section on rare outlier DMRs reports detecting underlying repeat expansions. The paper mentions genomic imprinting as a methylation mechanism and annotates imprinting control centers in its Methods, but our copy does not report identifying pathogenic variants in imprinting disorders. Repeat-expansion detection also came from outlier DMR analysis, not episignature screening. (LLM, conf=0.84)

  cites [142] LaFlamme, C. W. et al. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement. Nat. Commun. 15, 6524 (2024). sourceExperimental — accuracy not yet measured
• Partly supported

  Section 4.1 says episignature analysis can be used as a reflex test for a variant of unknown significance, supporting its potential to help clarify a variant’s significance. The cited paper does not establish the claim about identifying pathogenic variants in imprinting or repeat-expansion disorders, or address DEE episignatures specifically. (LLM, conf=0.82)

  cites [179] Levy, M. A. et al. Functional correlation of genome-wide DNA methylation profiles in genetic neurodevelopmental disorders. Hum. Mutat. 43, 1609–1628 (2022). sourceExperimental — accuracy not yet measured

In the paper

“Parents with mosaic levels <13% were unaffected and those with higher levels had febrile seizures or epilepsy.”

What the sources say

• Partly supported

  The TO THE EDITOR section reports that mosaicism levels broadly correlated with disease severity among four affected parents and that six families with unaffected parents had parental mosaicism. It does not establish a 13% cutoff separating unaffected parents from those with febrile seizures or epilepsy; 12.9% is reported as the mean mosaicism level, not a threshold. (LLM, conf=0.82)

  cites [175] Myers, C. T. et al. Parental mosaicism in “de novo” epileptic encephalopathies. N. Engl. J. Med. 378, 1646–1648 (2018). This study found that 8% of patients with a DEE thought to have a de novo pathogenic variant had a parent who was mosaic for their pathogenic variant, carrying significant reproductive counselling implications. sourceExperimental — accuracy not yet measured

In the paper

“Gene panels have been extensively used but only capture a subset of all >900 DEE genes, thereby failing to identify causative variants in genes that have not been sequenced 26 .”

What the sources say

• Partly supported

  The Introduction says epilepsy gene panels are routine diagnostic tests and that differences between panels could lead to missed genetic diagnoses. The Results report that clinical panels contain 144–511 genes, supporting the claim that each covers only a subset. But the paper reports 825 genes associated with a DEE phenotype out of 926 curated monogenic epilepsy genes—not more than 900 DEE genes (Results, “Monogenic epilepsy genes and insights”; page unavailable). (LLM, conf=0.90)

  cites [26] Oliver, K. L. et al. Genes4Epilepsy: an epilepsy gene resource. Epilepsia 64, 1368–1375 (2023). This study identified 926 known monogenic epilepsy genes in 2023 and showed that 825 genes were associated with DEEs; since publication, >1,000 genes have been listed on the publicly accessible database. sourceExperimental — accuracy not yet measured

In the paper

“Next generation sequencing has transformed our understanding of the aetiologies of the DEEs, enabling identification of their cause in 50% of patients 166,167 .”

What the sources say

• Partly supported

  The Introduction describes next-generation sequencing as a way to investigate many genes, and the Results (Economic modelling) show that adding targeted whole-exome sequencing increased diagnostic yield in infants with severe epilepsy. But the model’s 56% figure is the yield of an entire diagnostic pathway, not the proportion diagnosed by sequencing; the Results (Etiology) report a 32% yield for non-chromosomal genetic testing among infants investigated after epilepsy onset. The paper therefore supports sequencing’s diagnostic value, but not the claim that it identifies the cause in 50% of patients with DEEs. (LLM, conf=0.88)

  cites [166] Howell, K. B. et al. A population-based cost-effectiveness study of early genetic testing in severe epilepsies of infancy. Epilepsia 59, 1177–1187 (2018). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Diagnostic yield) report a 50% yield—16 of 32 patients—for the study’s trio exome-sequencing arm, and the Discussion links sequencing to identifying genetic causes of epileptic encephalopathy. The claim extends that cohort-specific result to patients with DEEs generally; the Introduction instead describes a 20%–40% improvement in diagnostic yield across prior studies. (LLM, conf=0.87)

  cites [167] Palmer, E. E. et al. Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: evidence of clinical utility and cost effectiveness. Mol. Genet. Genom. Med. 6, 186–199 (2018). sourceExperimental — accuracy not yet measured

In the paper

“A 2023 genome analysis of infants with seizures beginning in the first year of life identified a genetic cause in 43% of 100 infants, and all had implications for disease management 157 .”

What the sources say

• Partly supported

  The Results report genetic diagnoses in 43 of 100 infants with new-onset epilepsy. They report clinical utility for 42 of the 43 diagnosed infants, with treatment affected in 24; all families received genetic counselling. Thus, the claim that all diagnoses had implications for disease management overstates the finding. (LLM, conf=0.91)

  cites [157] D’Gama, A. M. et al. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. Lancet Neurol. 22, 812–825 (2023). This international collaborative study analysed the yield of rapid genome sequencing in infants presenting with seizures in the first year of life and highlighted the utility in determining management, prognostic and reproductive counselling. sourceExperimental — accuracy not yet measured

In the paper

“Treatment-emergent adverse events occurred in 43 of 50 (86%) patients in the ganaxolone group and in 45 of 51 (88%) patients in the placebo group 192 .”

What the sources say

• Supported

  Table 3 (Additional information) lists 43 of 50 ganaxolone patients (86%) and 45 of 51 placebo patients (88%) as having any treatment-emergent adverse event. The Results section reports the same counts and percentages. (LLM, conf=0.95)

  cites [192] Knight, E. M. P. et al. Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 21, 417–427 (2022). source

In the paper

“The higher dose of fenfluramine was associated with a significantly greater likelihood of achieving a >50% (68% versus 12% placebo) and a >75% reduction (50% versus 2% placebo) in convulsive seizure frequency.”

What the sources say

• Supported

  The Seizure Frequency section reports that 68% of patients receiving the higher 0.7 mg/kg/day dose achieved a ≥50% reduction in convulsive seizures, versus 12% on placebo (P<0.0001). It also reports significantly higher ≥75% responder rates, and the Additional information section gives a relative risk of 20 at that threshold, consistent with 50% versus approximately 2% on placebo. The paper uses ≥ rather than > for both thresholds. (LLM, conf=0.90)

  cites [197] Lagae, L. et al. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet 394, 2243–2254 (2019). This randomized controlled trial showed that fenfluramine is highly efficacious in Dravet syndrome, highlighting that trials targeting a repurposed drug in specific epilepsy syndrome can offer major improvements in clinical care. source

In the paper

“However, the SCB topiramate can be useful in Dravet syndrome 181 , whereas others, such as lamotrigine and phenytoin, may exacerbate seizures in some patients and be helpful in others 208,209 .”

What the sources say

• Partly supported

  The Results section (page unavailable) says lamotrigine can exacerbate seizures but may have a limited role in adults with refractory Dravet syndrome. It also says phenytoin may help in status epilepticus, but does not say that phenytoin exacerbates seizures in some patients. The topiramate clause has a separate citation and is not assessed here. (LLM, conf=0.86)

  cites [181] Wirrell, E. C. et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia 63, 1761–1777 (2022). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that lamotrigine has been associated with seizure exacerbation but reduced seizures in the three patients described. It lists phenytoin among drugs that worsen seizures; it does not say phenytoin can help some patients. The topiramate statement has a separate citation and is not assessed here. (LLM, conf=0.88)

  cites [208] Dalic, L., Mullen, S. A., Roulet Perez, E. & Scheffer, I. Lamotrigine can be beneficial in patients with Dravet syndrome. Dev. Med. Child. Neurol. 57, 200–202 (2015). sourceExperimental — accuracy not yet measured
• Supported

  The citation to this paper follows the claim about lamotrigine and phenytoin, not the separate topiramate claim. In the Discussion (page not supplied), the paper reports both seizure exacerbation and improvement with phenytoin, and says lamotrigine was thought to worsen seizures but benefited three patients. (LLM, conf=0.91)

  cites [209] Zographos, G. A., Russ-Hall, S. J. & Scheffer, I. E. Does long-term phenytoin have a place in Dravet syndrome? Ann. Clin. Transl. Neurol. 9, 2036–2040 (2022). source

In the paper

“The severity of epilepsy in patients with DEEs should not reduce the focus on comorbidities as cognitive, psychiatric (such as ASD, anxiety, mood and behavioural disorders, psychosis), motor and medical disorders occur frequently 110,152,153,156,215 .”

What the sources say

• Partly supported

  The Results (Neurodevelopment and behavioral issues) report frequent intellectual disability, behavioral problems, and ASD; the Discussion also identifies ataxia as a common comorbidity of SYNGAP1-DEE. The paper studies SYNGAP1-DEE specifically, not DEEs generally, and the passages do not establish that anxiety, mood disorders, or psychosis occur frequently. (LLM, conf=0.86)

  cites [110] Vlaskamp, D. R. M. et al. SYNGAP1 encephalopathy: a distinctive generalized developmental and epileptic encephalopathy. Neurology 92, E96–E107 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion (p. 9) reports frequent cognitive impairment, ASD or autistic features, behavioral problems, and motor and medical comorbidities in patients with NEXMIF encephalopathy. It does not establish that these comorbidities occur frequently across DEEs generally, or report anxiety, mood disorders, and psychosis as frequent in its cohort. (LLM, conf=0.86)

  cites [152] Stamberger, H. et al. NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genet. Med. 23, 363–373 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion and Conclusions (pages not supplied) support continued attention to psychiatric comorbidities in PCDH19 Girls Clustering Epilepsy: behavioral problems and ASD can be disabling even after seizures abate, and the authors recommend routine monitoring for later-onset schizophrenia. The paper does not establish that cognitive, psychiatric, motor, and medical disorders all occur frequently across patients with DEEs generally. (LLM, conf=0.86)

  cites [153] Vlaskamp, D. R. M. et al. Schizophrenia is a later-onset feature of PCDH19 girls clustering epilepsy. Epilepsia 60, 429–440 (2019). sourceExperimental — accuracy not yet measured
• Partly supported

  The Comorbid conditions section (p. 2) reports autism-spectrum characteristics, developmental slowing and behavior problems in children with Dravet syndrome; the Discussion (p. 5) calls for integrated care addressing developmental, orthopedic and other medical needs. The paper supports continued attention to comorbidities despite severe epilepsy, but it studies Dravet syndrome rather than DEEs generally and does not establish that anxiety, mood disorders or psychosis occur frequently. (LLM, conf=0.88)

  cites [156] Skluzacek, J. V., Watts, K. P., Parsy, O., Wical, B. & Camfield, P. Dravet syndrome and parent associations: the IDEA League experience with comorbid conditions, mortality, management, adaptation, and grief. Epilepsia 52, 95–101 (2011). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [215] Villas, N., Meskis, M. A. & Goodliffe, S. Dravet syndrome: characteristics, comorbidities, and caregiver concerns. Epilepsy Behav. 74, 81–86 (2017). source

In the paper

“Subsequent studies of fenfluramine in Dravet syndrome demonstrated dosedependent clinically meaningful effects on regulating behaviour, emotion, cognition, and everyday executive functions in preschool age 199 and sustained efficacy and safety in children, adolescents and adults in real-world practice 200,201 .”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [199] Bishop, K. I. et al. Fenfluramine treatment is associated with improvement in everyday executive function in preschool-aged children (<5 years) with Dravet syndrome: a critical period for early neurodevelopment. Epilepsy Behav. 138, 108994 (2023). source
• ?Not checked — no full text of the sourcecites [200] Specchio, N. et al. Efficacy and safety of fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a real-world study. Epilepsia 61, 2405–2414 (2020). source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [201] Guerrini, R. et al. An examination of the efficacy and safety of fenfluramine in adults, children, and adolescents with Dravet syndrome in a real-world practice setting: a report from the Fenfluramine European Early Access Program. Epilepsia Open. 7, 578–587 (2022). source

In the paper

“In this RCT, responder rates were greater with higher-dose everolimus than with placebo; however, they were perhaps less compelling than one might expect for a precision therapy (40% vs 15.1%, p<0.0001) 131 .”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [131] French, J. A. et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet 388, 2153–2163 (2016). This randomized controlled trial analysed the efficacy of an mTOR inhibitor for drug-resistant focal epilepsy in tuberous sclerosis, showing that a precision therapy approach is efficacious for this disease. source

In the paper

“Pre-hospital benzodiazepine administration may be effective in controlling repetitive seizures or status epilepticus and avoid hospitalization 212,213 .”

What the sources say

• Partly supported

  The Key Points (page unavailable) describe benzodiazepine delivery in pre-hospital settings, and the Midazolam section says newer formulations are used to treat prolonged seizures, seizure clusters and status epilepticus. Our copy does not say that pre-hospital treatment can avoid hospitalization; searches for hospitalization and hospital admission did not establish that outcome. (LLM, conf=0.82)

  cites [212] Kienitz, R. et al. Benzodiazepines in the management of seizures and status epilepticus: a review of routes of delivery, pharmacokinetics, efficacy, and tolerability. CNS Drugs 36, 951–975 (2022). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction identifies seizure clusters as acute repetitive seizures, and the Conclusion says community-administered nasal rescue treatment can help control clusters and potentially reduce reliance on emergency services. Treating Seizure Clusters says rescue medication may reduce the onset of status epilepticus and the need for emergency transport. The paper does not establish that pre-hospital treatment controls status epilepticus once it has begun or avoids hospitalization specifically. (LLM, conf=0.84)

  cites [213] Penovich, P. E., Rao, V. R., Long, L., Carrazana, E. & Rabinowicz, A. L. Benzodiazepines for the treatment of seizure clusters. CNS Drugs 38, 125–140 (2024). sourceExperimental — accuracy not yet measured

In the paper

“In contrast to most RCTs, the clinical response increased over time as measured in the open-label extension study of patients on everolimus for ≥48 weeks, postulated to be due to a disease-modifying effect 204 .”

What the sources say

• Partly supported

  The Results report that response rates increased from 31% at week 18 to 46.6% at one year and 57.7% at two years. The introduction says seizure improvement might increase over time because everolimus addresses the underlying pathophysiology of TSC, and states that all patients had completed at least 48 weeks of the extension phase. Our copy does not establish the comparison with most RCTs. (LLM, conf=0.85)

  cites [204] Franz, D. N. et al. Everolimus for treatment-refractory seizures in TSC: extension of a randomized controlled trial. Neurol. Clin. Pract. 8, 412–420 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Studies typically incorporate several validated questionnaires to assess different aspects of HRQOL, such as the Epilepsy & Learning Disability Quality of Life Questionnaire 220 , the Impact of Pediatric Epilepsy Scale 221 , the Pediatric Quality of Life Inventory 222 , the Parental Stress Index 223 and the Strength and Difficulties Questionnaire 224 .”

What the sources say

• ?Not checked — no full text of the sourcecites [220] Buck, D., Smith, M., Appleton, R., Baker, G. A. & Jacoby, A. The development and validation of the Epilepsy and Learning Disabilities Quality of Life (ELDQOL) scale. Epilepsy Behav. 10, 38–43 (2007). source
• Supported

  Citation 221 identifies the Impact of Pediatric Epilepsy Scale, rather than supporting the other questionnaires in the list. The Conclusions describe the IPES as a measurement tool for how childhood epilepsy affects the child and family, and the paper reports its reliability and validity. (LLM, conf=0.93)

  cites [221] Camfield, C., Breau, L. & Camfield, P. Impact of pediatric epilepsy on the family: a new scale for clinical and research use. Epilepsia 42, 104–112 (2001). source
• ?Not checked — no full text of the sourcecites [222] Varni, J. W., Seid, M. & Rode, C. A. The PedsQL: measurement model for the pediatric quality of life inventory. Med. Care 37, 126–139 (1999). source

In the paper

“The most responsive seizure type was the generalized tonic-clonic seizure (GTCS) in 120 of 263 [46%] patients, with a decrease in frequency of 45.7% and 58.2% in the higher and lower dose groups, respectively.”

What the sources say

• Supported

  The Results (Additional Secondary Outcomes) state that GTC seizures occurred at baseline in 120 of 263 patients (46%) and were more responsive to fenfluramine than other seizure types. During the combined titration and maintenance period, GTC frequency fell by 45.7% in the 0.7-mg/kg/d group and 58.2% in the 0.2-mg/kg/d group, matching the claimed higher- and lower-dose figures. (LLM, conf=0.95)

  cites [202] Knupp, K. G. et al. Efficacy and safety of fenfluramine for the treatment of seizures associated with Lennox–Gastaut syndrome: a randomized clinical trial. JAMA Neurol. 79, 554–564 (2022). source

In the paper

“Identification of the efficacy of fenfluramine in Dravet syndrome followed the observation that it was particularly beneficial in children with drug-resistant, self-induced photosensitive epilepsy 195 , resulting in seizure freedom in 7 of 12 patients with Dravet syndrome in one study 196 .”

What the sources say

• ?Not checked — no full text of the sourcecites [195] Casaer, P. & Boel, M. Fenfluramine as a potential antiepileptic drug. Epilepsia 43, 205–206 (2002). source
• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [196] Ceulemans, B. et al. Successful use of fenfluramine as an add-on treatment for Dravet syndrome. Epilepsia 53, 1131–1139 (2012). source

In the paper

“Classification of DEEs into syndromes has enabled condition-specific patient advocacy groups to form, facilitating research participation of carers 215,219 .”

What the sources say

• ?Not checked — no full text of the sourcecites [215] Villas, N., Meskis, M. A. & Goodliffe, S. Dravet syndrome: characteristics, comorbidities, and caregiver concerns. Epilepsy Behav. 74, 81–86 (2017). source
• Partly supported

  The Methods (Survey development and Participants; page unavailable) name three Dravet syndrome patient advocacy groups and describe recruiting caregivers through association meetings and an online survey. This supports the groups’ role in carers’ research participation, but the paper does not say that classifying DEEs into syndromes enabled those groups to form. (LLM, conf=0.86)

  cites [219] Chemaly, N. et al. A European pilot study in Dravet syndrome to delineate what really matters for the patients and families. Epilepsia Open. 9, 388–396 (2021). sourceExperimental — accuracy not yet measured

In the paper

“The open-label extension phase of this study, in which 142 patients completed their final visit after 12 months 203 , confirmed GTCS to be the most responsive seizure type, with median reductions over the entire extension period of 48.8%, whereas tonic seizures reduced by 35.8%.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [203] Knupp, K. G. et al. Fenfluramine provides clinically meaningful reduction in frequency of drop seizures in patients with Lennox–Gastaut syndrome: interim analysis of an open-label extension study. Epilepsia 64, 139–151 (2023). source

In the paper

“Different genetic DEEs have different risks of convulsive and non-convulsive status epilepticus and death 19 ; understanding these risks informs diagnosis, prognostic counselling and management strategies.”

What the sources say

• Supported

  The Discussion (Table 4, p. e1715) distinguishes CSE, NCSE, and mortality risks across the studied genetic DEEs. The Discussion also says these findings will inform clinical discussions and management, while the Abstract says understanding the risks can enable earlier diagnosis. (LLM, conf=0.93)

  cites [19] Donnan, A. M., Schneider, A. L., Russ-Hall, S., Churilov, L. & Scheffer, I. E. Rates of status epilepticus and sudden unexplained death in epilepsy in people with genetic developmental and epileptic encephalopathies. Neurology 100, e1712–e1722 (2023). This study examined the frequency of convulsive and non-convulsive status epilepticus and mortality rates in different genetic DEEs, informing counselling of families, diagnosis and clinical management. source

In the paper

“This study employs polygenic risk scores for longevity and intellect in a relatively small cohort of adults with Dravet syndrome, providing the first insights into the role of common variation in explaining these phenotypic features.”

What the sources say

• ?Could not verify

  The Methods (Statistical analysis) describe comparisons of clinical visits and calculation of mortality rates, while the Results report cognitive outcomes. Searches for polygenic risk scores, longevity and intellect, and common variation found no passage describing a polygenic analysis or its findings. (LLM, conf=0.77)

  cites [245] Balestrini, S. et al. A registry for Dravet syndrome: the Italian experience. Epilepsia Open. 8, 517–534 (2023). sourceExperimental — accuracy not yet measured

In the paper

“Although 90% of adults with TSC remained on anti-seizure medication, almost 40% did not have neurological follow-up 231”

What the sources say

• Partly supported

  The Discussion reports that 90% of the study patients still received antiepileptic therapy and almost 40% lacked regular follow-up by a neurologist. The claim omits “regular” and applies the figures to adults with TSC generally, whereas the study concerned adults with TSC who developed epilepsy during childhood (Discussion). (LLM, conf=0.86)

  cites [231] Bar, C. et al. Experience of follow-up, quality of life, and transition from pediatric to adult healthcare of patients with tuberous sclerosis complex. Epilepsy Behav. 96, 23–27 (2019). sourceExperimental — accuracy not yet measured

In the paper

“It is also unclear whether differences in severity of cognitive impairment among family members with the same SCN1A pathogenic variant, where one individual has Dravet syndrome and another has GEFS+, is due to genomic background, environmental factors or more severe seizures in the individual with Dravet syndrome 244 .”

What the sources say

• Partly supported

  The Introduction says that relatives with the same SCN1A variant can have GEFS+ or Dravet syndrome, and the Results (PRS analyses) say that cognitive phenotypes can vary within families and that factors affecting cognition are debated. The paper considers genomic background, but these passages do not specifically identify environmental factors or more severe seizures as competing explanations for the cognitive difference between those relatives. Page numbers were not provided in our copy. (LLM, conf=0.86)

  cites [244] Martins Custodio, H. et al. Widespread genomic influences on phenotype in Dravet syndrome, a ‘monogenic’ condition. Brain 146, 3885–3897 (2023). This study employed polygenic risk scores for longevity and intellect in a relatively small cohort of adults with Dravet syndrome, providing the first insights into the role of common variation in explaining these phenotypic features. sourceExperimental — accuracy not yet measured

In the paper

“Parents of children with LGS, the vast majority mothers, reported constant anxiety, difficulties in accessing childcare, restriction of social life and poor mental health 229,230 .”

What the sources say

• Supported

  The Procedure (p. 2) reports that 36 of the 40 interviewed parents were mothers. The Discussion (p. 6) reports constant anxiety, difficulty finding appropriate childcare, restricted social lives, and an association with poorer mental health; it does not claim that caring for a child with LGS caused the poorer mental health. (LLM, conf=0.94)

  cites [229] Gallop, K. et al. Lennox–Gastaut syndrome (LGS): development of conceptual models of health-related quality of life (HRQL) for caregivers and children. Seizure 19, 23–30 (2010). source
• Partly supported

  The Results section on health-related quality of life reports anxiety in 58% of LGS parent caregivers, below-average mental-health scores, and social impacts. It does not say the anxiety was constant, that the vast majority of parents were mothers, or that they had difficulty accessing childcare. Page numbers are not available in our copy. (LLM, conf=0.86)

  cites [230] Strzelczyk, A., Zuberi, S. M., Striano, P., Rosenow, F. & Schubert-Bast, S. The burden of illness in Lennox–Gastaut syndrome: a systematic literature review. Orphanet J. Rare Dis. 18, 42 (2023). sourceExperimental — accuracy not yet measured

In the paper

“and are more likely to resign from employment resulting in greater financial burden for the caregiver's family 228 .”

What the sources say

• Partly supported

  Section 3.6 reports that mothers caring for patients with Dravet syndrome were more likely to quit work than those in the comparison groups, and that caregivers in the Dravet group had the highest estimated lost productivity. Section 2.3 says these indirect costs were calculated from a societal perspective; the paper does not establish the resulting financial burden on individual caregivers’ families. Page numbers are not available in our copy. (LLM, conf=0.85)

  cites [228] Strzelczyk, A. et al. A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany. Epilepsia 60, 1697–1710 (2019). sourceExperimental — accuracy not yet measured

In the paper

“Dosing is an important issue, which requires a delicate balance to ensure that a GOF phenotype is not turned into a LOF phenotype, as many genes demonstrate severe phenotypes with both types of dysfunction 34 .”

What the sources say

• Partly supported

  The Functional studies section (p. 13) identifies both gain-of-function and loss-of-function SCN2A mutations in children with epilepsy. The Seizure outcome and treatment effects section (p. 17) discusses possible seizure aggravation when sodium-channel blockers further reduce activity in a loss-of-function disorder. The paper does not address gene-therapy dosing or show that treatment can turn a gain-of-function phenotype into a loss-of-function phenotype; its evidence concerns SCN2A rather than many genes. (LLM, conf=0.87)

  cites [34] Wolff, M. et al. Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140, 1316–1336 (2017). sourceExperimental — accuracy not yet measured

In the paper

“This international collaborative study analysed the yield of rapid genome sequencing in infants presenting with seizures in the first year of life and highlighted the utility in determining management, prognostic and reproductive counselling.”

What the sources say

• Supported

  The Methods (Study design and cohort; page unavailable) specify seizure onset before 12 months of age. The Findings report a 43% diagnostic yield and state that genetic diagnoses informed treatment, prognosis, and recurrence-risk counselling, supporting the claimed clinical utility. (LLM, conf=0.94)

  cites [157] D’Gama, A. M. et al. Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study. Lancet Neurol. 22, 812–825 (2023). This international collaborative study analysed the yield of rapid genome sequencing in infants presenting with seizures in the first year of life and highlighted the utility in determining management, prognostic and reproductive counselling. source

In the paper

“The International League Against Epilepsy's (ILAE) definition of an epileptic encephalopathy is that the epileptic activity itself contributes to severe cognitive and, sometimes, behavioural impairment, beyond what might be expected from the underlying pathology alone, and that these can worsen over time 1 .”

What the sources say

• ?Not checked — no full text of the sourcecites [1] Berg, A. T. et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia 51, 676–685 (2010). source

In the paper

“One of the best examples is Lennox-Gastaut syndrome (LGS), defined in 1945 on the basis of tonic and atypical absence seizures, intellectual disability and slow spike-wave on EEG 5,6 .”

What the sources say

• ?Not checked — no full text of the sourcecites [5] Lennox, W. G. The petit mal epilepsies; their treatment with tridione. J. Am. Med. Assoc. 129, 1069–1074 (1945). source
• ?Not checked — no full text of the sourcecites [6] Gastaut, H. et al. Childhood epileptic encephalopathy with diffuse slow spike-waves (otherwise known as “petit mal variant”) or Lennox syndrome. Epilepsia 7, 139–179 (1966). source

In the paper

“Although cardiac dysfunction as evidenced by altered heart rate variability has been shown in Dravet syndrome, there is no definite evidence that the high SUDEP rate has a cardiac basis 21 .”

What the sources say

• ?Not checked — no full text of the sourcecites [21] Myers, K. A. et al. Heart rate variability in epilepsy: a potential biomarker of sudden unexpected death in epilepsy risk. Epilepsia 59, 1372–1380 (2018). source

In the paper

“From the first identification of epilepsy genes, CHRNA4, KCNQ2 and SCN1B using family studies in the 1990s, genetic discoveries have shed light on disease mechanisms [22][23][24][25] .”

What the sources say

• ?Not checked — no full text of the sourcecites [22] Steinlein, O. K. et al. A missense mutation in the neuronal nicotinic acetylcholine receptor α4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat. Genet. 11, 201–203 (1995). source
• ?Not checked — no full text of the sourcecites [23] Biervert, C. et al. A potassium channel mutation in neonatal human epilepsy. Science 279, 403–406 (1998). source
• ?Not checked — no full text of the sourcecites [24] Singh, N. A. et al. A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns. Nat. Genet. 18, 25–29 (1998). source

In the paper

“Variants affecting GluN2B, encoded by GRIN2B, cause intellectual disability and/or autism spectrum disorder (ASD) in all patients with a range of DEEs, including IESS 83,84 , and a hyperkinetic movement disorder.”

What the sources say

• ?Not checked — no full text of the sourcecites [83] Endele, S. et al. Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat. Genet. 42, 1021–1026 (2010). source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [84] Platzer, K. & Lemke, J. R. GRIN2B-Related Neurodevelopmental Disorder (GeneReviews, 2021).

In the paper

“A recent Phase 2A trial in 24 children with LOF GRIN variants showed substantial improvements in motor function and improved seizures in one patient 92 .”

What the sources say

• ?Not checked — no full text of the sourcecites [92] Julia-Palacios, N. et al. L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study. Brain 147, 1653–1666 (2024). source

In the paper

“Pathogenic variants in SLC6A1 which encodes GABA transporter 1 (hGAT-1), responsible for clearing GABA from the synaptic cleft, also lead to activation of extra-synaptic GABA receptors and increased tonic inhibition, resulting in epilepsy with myoclonicatonic seizures 76 .”

What the sources say

• ?Not checked — no full text of the sourcecites [76] Carvill, G. L. et al. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am. J. Hum. Genet. 96, 808–815 (2015). source

In the paper

“Neurodevelopmental disorders and epilepsy are common, 88% of patients have epilepsy and 40% IESS 125 .”

What the sources say

• ?Not checked — no full text of the sourcecites [125] Gupta, A. et al. Epilepsy and neurodevelopmental comorbidities in tuberous sclerosis complex: a natural history study. Pediatr. Neurol. 106, 10–16 (2020). source

In the paper

“Biallelic pathogenic variants in UBA5 cause DEEs, severe developmental impairment, hypotonia, spasticity, microcephaly, and growth failure 144 .”

What the sources say

• ?Not checked — no full text of the sourcecites [144] Muona, M. et al. Biallelic variants in UBA5 link dysfunctional UFM1 ubiquitin-like modifier pathway to severe infantile-onset encephalopathy. Am. J. Hum. Genet. 99, 683–694 (2016). source

In the paper

“A still common example is the use of SCB, carbamazepine or oxcarbazepine in infants with hemiclonic or tonic-clonic seizures who have undiagnosed Dravet syndrome, as these specific ASMs commonly cause seizure exacerbation with adverse developmental consequences 159 .”

What the sources say

• ?Not checked — no full text of the sourcecites [159] Scheffer, I. E. & Liao, J. Deciphering the concepts behind “epileptic encephalopathy” and “developmental and epileptic encephalopathy”. Eur. J. Paediatr. Neurol. 24, 11–14 (2020). source

In the paper

“It typically takes time for the full syndromic picture to emerge, during which the child often shows developmental slowing or regression.”

In the paper

“Diagnosis of a DEE syndrome informs aetiological investigations, prognostic and genetic counselling, and selection of therapeutic approaches.”

In the paper

“These findings reinforce the need to consider a genetic aetiology for all structural changes in the brain.”

In the paper

“A DEE can be distinguished from an epileptic encephalopathy as a pure epileptic encephalopathy occurs in the context of normal development before either seizure onset or development of frequent epileptiform activity on EEG.”

In the paper

“Both hyperventilation and intermittent photic stimulation increase the likelihood of eliciting epileptiform activity (such as generalized spike-wave) and sometimes seizures (typically absence seizures if hyperventilation is well performed, which is often not possible for these patients).”

In the paper

“Furthermore, a gene can be associated with different DEE syndromes that reflect GOF or LOF and, therefore, need therapies with the mode of action tailored to the underlying dysfunction.”

In the paper

“Observational studies suggest that appropriate therapies improve developmental outcomes, but long-term outcome is rarely normal and a multimorbidity picture remains usual 27 .”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [27] Dravet C. et al. in Epileptic Syndromes in Infancy, Childhood and Adolescence 6th edn (eds Bureau, M. et al.) 139–171 (Libbey Eurotext, 2019).

In the paper

“One should aim to identify both the DEE epilepsy syndrome diagnosis and aetiology for each patient, as they provide complementary information that critically inform patient management.”

In the paper

“Of note, a serious diagnosis, such as a DEE, in infancy carries considerable consequences that require proactive clinical management.”

In the paper

“Management of the DEEs requires a focus on both seizure control and comorbidities.”

In the paper

“In Dravet syndrome, a RCT of stiripentol demonstrated clear efficacy 193 , after initially being trialled in drug-resistant epilepsy.”

What the sources say

• ?Not checked — no full text of the sourcecites [193] Chiron, C. et al. Stiripentol in severe myoclonic epilepsy in infancy: a randomised placebo-controlled syndrome-dedicated trial. STICLO study group. Lancet 356, 1638–1642 (2000). source

In the paper

“A holistic approach involves a multidisciplinary team to provide appropriate therapies to mitigate developmental, psychiatric, and behavioural challenges.”

In the paper

“The full gamut of investigations is often not available in low-income and middle income settings, where access may be limited to EEG and imaging studies, and a genetic aetiology cannot be identified due to lack of availability of genetic testing.”

In the paper

“Testing of blood or saliva would not detect mosaicism limited to gonads, so genetic counselling should always discuss this possibility and potential testing of a subsequent pregnancy should be considered (eg with IVF, chorionic villus sampling or amniocentesis).”

In the paper

“With recent scientific insights into the marked genetic heterogeneity and phenotype-genotype complexity of DEEs, it is unsurprising that few evidence-based trials to guide therapy currently exist.”

In the paper

“In Dravet syndrome and PCDH19epilepsies, fever or hyperthermia (even simply a hot environment or hot bath) are well-recognised seizure triggers, and may have even more serious consequences.”

In the paper

“The development of composite endpoints for DEE trials, acknowledging the importance of improving comorbidities as well as reducing seizure frequency, is a new area of trial design 225 .”

What the sources say

• ?Not checked — no full text of the sourcecites [225] Nabbout, R. et al. Development and content validation of a preliminary core set of patient- and caregiver-relevant outcomes for inclusion in a potential composite endpoint for Dravet syndrome. Epilepsy Behav. 78, 232–242 (2018). source

In the paper

“Health-related quality of life (HRQOL) studies measure the effect of chronic disease on an individual's physical, social and mental well-being 218 .”

What the sources say

• ?Not checked — no full text of the sourcecites [218] Sabaz, M. et al. Validation of a new quality of life measure for children with epilepsy. Epilepsia 41, 765–774 (2000). source

In the paper

“Owing to the trial design, one cannot infer that this combination of ASMs is necessarily the most effective; real-world data may show other combinations to be more effective or have improved tolerability.”

In the paper

“A posthoc analysis of patients <18 years showed that children <6 years of age had greater benefit, suggesting that this precision therapy may be more beneficial if commenced earlier 205 .”

What the sources say

• ?Not checked — no full text of the sourcecites [205] Curatolo, P. et al. Management of epilepsy associated with tuberous sclerosis complex: updated clinical recommendations. Eur. J. Paediatr. Neurol. 22, 738–748 (2018). source

In the paper

“In children with DEEs, QOL measures extend to parents, carers, and the wider family, as there is lifelong caregiver responsibility and burden.”

In the paper

“This is a delicate matter, as simply adopting a protocol reduces mortality and morbidity, although there is little evidence to show that one of the numerous recommended protocols is better than another 211 .”

What the sources say

• ?Not checked — no full text of the sourcecites [211] Guerrini, R. Epilepsy in children. Lancet 367, 499–524 (2006). source

In the paper

“DEEs have, by definition, developmental effects, which are unlikely to be reversed postnatally; this limitation likely applies to developmental genes, receptors and channels.”

In the paper

“An alternative to DNA is to target messenger RNA (mRNA) using antisense oligonucleotides, which can be administered intrathecally to either inhibit or increase mRNA transcription, alter mRNA splicing or increase mRNA degradation 236 .”

What the sources say

• ?Not checked — no full text of the sourcecites [236] Ersoz, E. & Demir-Dora, D. Unveiling the potential of antisense oligonucleotides: mechanisms, therapies, and safety insights. Drug. Dev. Res. 85, e22187 (2024). source

In the paper

“Although DEEs have a vast array of mainly genetic etiologies that alter different developmental processes and aspects of neural cell functioning, a shared consequence is impairment of higher cortical functions, in addition to drug-resistant seizures.”

In the paper

“That said, the widespread nature of neuronal dysfunction typical of DEE requires a delivery system capable of targeting the whole brain in a critical period before mature connections are in place.”

In the paper

“In humans, lack of a period of normal development in neonatal and infantile DEE make it difficult to determine any additive effect of seizures on cognitive outcome, but there are clear examples where improvement of seizure control or resolution of interictal EEG abnormalities ameliorate cognitive outcome.”

In the paper

“Mosaicism and X-linked disorders further complicate cellular targeting.”

In the paper

“Although severity varies across and within specific epilepsy syndromes and genetic diseases, language, memory, attention, and executive functions are usually impaired in the long term, with almost all patients having cognitive impairment and many have features of ASD.”

In the paper

“A clinical trial is ongoing in Dravet syndrome and CDKL5 deficiency disorder 241 .”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [241] US National Library of Medicine. ClinicalTrials.gov ClinicalTrials.gov/show/NCT02758626 (2023).

In the paper

“The prominent role of genes implicated in DEEs in early brain development indicates a considerable contribution of aetiology to cognitive outcome, so developmental impairment (compounded by slowing or regression) is inherent to DEEs.”