Epilepsy in Neuropediatrics
In this issue, epilepsy is not the exclusive, but a dominant topic. This justifies an editorial focus on the included articles.
Samanta gives a narrative review on advances in diagnosis and treatment of neonatal seizures. Neonatal seizures are a worrisome clinical sign for pediatric neurologists and neonatologists alike. Moreover, the substantial threat of acute and chronic encephalopathy is an emotional disaster for parents and caregivers. An orderly approach to a diagnostic workup is pertinent, because in many cases clarification of the underlying etiology will take time. Genetic, metabolic, and infectious causes are extremely diverse, which leave the treating physician always with a significant amount of insecurity if no cause is readily detected, since some of these causes are amendable by a specific treatment. All these topics are nicely covered in an easy to read and up to date review. Samanta covers clinical signs, seizure semiology, and neonatal electroencephalography (EEG). A comparison of studies reporting on differing sensitivity and specificity of conventional versus amplitude integrated EEG is also given. New randomized controlled trials (NEMO and NEOLEV2) are included in a proposed treatment algorithm for neonatal seizures. Finally, it is emphasized that in “idiopathic” neonatal seizures, a genetic cause may be detectable in up to 30% of cases. In some cases, these results will open a possibility of precision medicine (e.g., sodium channel blockers in KCNQ2-related epileptic encephalopathy), while in many other instances, they only relieve the clinician by providing certainty that “nothing was missed.”
An interesting paper on risk factors for mortality among newborns with neonatal seizures is provided by Tanous et al in this issue. This topic is difficult to investigate in a controlled fashion. There is only one prospective trial published, namely, by Glass et al. This, together with other less well-controlled series, is used as a comparator for the retrospective study by Tanous et al. The study was performed in a large cohort with a mix of two ethnically distinct populations in the northeast of Israel: one group featuring a high rate of consanguinity and one with an average rate. In this large retrospective single hospital series, 1.7 per 1000 live births developed neonatal seizures, with hypoxic ischemic encephalopathy as the most frequent cause. However, almost 30% of infants with neonatal seizures died in the first year, a number that is twice as large as in other reports. The authors show that in their series children with congenital brain malformations and other monogenetic disorders were overrepresented in the group with fatal outcome. The reported numbers exceed findings reported by Glass et al, but are in line with other publications specifically reporting on highly consanguineous populations.
The paper by Willimsky et al investigates sensitivity and specificity of next generation sequencing for monogenetic epilepsies and developmental and epileptic encephalopathies (DEE). Larger gene panels covering >25 kb are (of course) more sensitive than those <25 kb, but at the same time more results of unknown significance will be generated by the larger panels. The included number of patients in this study is rather modest (n = 190) and mode of analysis is technically heterogeneous. The authors divide their sample into patients with epilepsy only (non-DEE) and patients with DEE. In both samples, the detection rate increased when larger panels were compared with smaller ones. However, in the non-DEE group, this effect was clearly more pronounced and reached statistical significance. While this may also be partly attributable to differing sizes of both groups, the authors argue that in non-DEE patients, the increase in detection rate by larger gene panels is greater than in DEE patients, because in patients with DEE the gene candidates are fewer and better defined. Therefore, in a scenario of financial restrictions using a larger gene panel may be more cost efficient in non-DEE patients in a first-step approach of genetic workup.
Virtually as an exemplification of the article by Willimsky et al, Algahtani et al report on a new homozygous variant in HERGC2 in a consanguine Arab family. Three affected siblings in this family suffer from a severe DEE. HERC2 mutations were recently detected among Old Order Amish families (MIM #605837). The phenotype was initially described as an autosomal recessive developmental encephalopathy with similarities to Angelman syndrome. Only a few cases have been reported since its first description. The clinical spectrum is best characterized by a severe mental handicap with autistic features, with or without epilepsy. It is one those rare genes that will currently not be included in any (epilepsy) gene panel no matter how large.
Febrile infection-related epilepsy syndrome (FIRES) is probably the most malignant epileptic encephalopathy of childhood. A significant number of children with FIRES have died, while others have remained on intensive care for almost a year. The sudden onset of this irreversible “gray matter failure” resembles the most striking and most unparalleled feature of FIRES. There are only very few cases of children surviving FIRES without severe sequelae. Many suffer from continuous therapy resistant epilepsy. In 2011, Kramer et al published a series of 77 children reporting the apparently positive results of high-dose phenobarbital, benzodiazepines, and ketogenic diet in controlling status epilepticus. In this issue, Baba et al support this view and report on a girl who was treated with high-dose thiamylal (unavailable in Europe, closely related to thiopental) combined with parenteral ketogenic diet starting at day 6. Steroids, immunoglobulins, and benzodiazepines were also applied. The course of treatment in the intensive care unit was complicated; however, the child survived and is now seizure free since 15 months under a combination of clonazepam and lacosamide. The authors speculate that early administration of a high-dose phenobarbital derivate and early onset ketogenic diet might be responsible for the benign course of the epilepsy. Dosing regime and diet protocol are reported in detail.
This “epilepsy issue” is complemented by a book review on “Cataltepe O, Jallo GI, eds. Pediatric Epilepsy Surgery: Preoperative Assessment and Surgical Treatment” kindly provided by Georgia Ramantani.
I would now like to wish you inciting reading!
19 March 2021 (online)
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- 1 Samanta D. Recent advances in the diagnosis and treatment of neonatal seizures. Neuropediatrics 2021; 52 (02) 73-83
- 2 Tanous O, Watad M, Felszer-Fisch C, Peniakov M, Miron D, Salim R. Risk factors for mortality among newborns with neonatal seizures. Neuropediatrics 2021; 52 (02) 84-91
- 3 Glass HC, Shellhaas RA, Wusthoff CJ. et al; Neonatal Seizure Registry Study Group. Contemporary profile of seizures in neonates: a prospective cohort study. J Pediatr 2016; 174: 98-103.e1
- 4 Willimsky EK, Munzig A, Mayer K. et al. Next generation sequencing in pediatric epilepsy using customized panels: size matters. Neuropediatrics 2021; 52 (02) 92-97
- 5 Algahtani H, Shirah B, Daghistani M, Al-Qahtani MH, Abdulkareem AA, Naseer MI. A novel mutation in HERC2 gene in a patient with global developmental delay, intellectual disability, and refractory seizures. Neuropediatrics 2020; 52 (02) 150-152
- 6 Kramer U, Chi CS, Lin KL. et al. Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children. Epilepsia 2011; 52 (11) 1956-1965
- 7 Baba S, Okanishi T, Ohsugi K. et al. Possible role of high-dose barbiturates and early administration of parenteral ketogenic diet for reducing development of chronic epilepsy in febrile infection related epilepsy syndrome: a case report. Neuropediatrics 2021; 52 (02) 133-137
- 8 Ramantani G. Pediatric epilepsy surgery: preoperative assessment and surgical treatment (book review). Neuropediatrics 2021; 52 (02) 154