Diagnosis switching and outcomes in a cohort of patients with potential epilepsy with myoclonic-atonic seizures

Abstract

INTRODUCTION: There is overlap in the electroclinical features of many childhood epilepsy syndromes, especially those presenting with multiple seizure types, such as epilepsy with myoclonic-atonic seizures (EMAS) and Lennox-Gastaut syndrome (LGS). This study aimed to determine the frequency of diagnosis switching and the factors influencing epilepsy syndrome diagnosis in a cohort of children with possible EMAS, as well as to explore the relationship between epilepsy syndromes diagnoses, key electroclinical features, and clinically relevant outcomes. METHODS: This is a cross-sectional retrospective chart review of children treated at the Children’s Hospital of Colorado with a potential diagnosis of EMAS. RESULTS: There were 77 patients that met eligibility criteria, including 39% (n=30) with an initial diagnosis of EMAS and 74% (n=57) with a final diagnosis of EMAS. On average, for the 65% of patients who received more than one epilepsy diagnosis, the first, second, and third diagnoses were received within one year, three years, and ten years after epilepsy onset, respectively. Final diagnosis was significantly related to obtaining at least a six-month period of seizure freedom, p=0.03. Classic LGS traits, including paroxysmal fast activity, slow spike-and-wave, and tonic seizures were present in 50% of the overall cohort, although a minority of these patients had a final diagnosis of LGS. However, the presence of more LGS traits was associated with a higher likelihood of ongoing seizures. Adjusted for age of epilepsy onset, seizure freedom was half as likely for every additional LGS trait observed (0.49[0.31, 0.77], p=0.002). CONCLUSION: Current epilepsy syndrome classification has reduced applicability due to overlapping features. This results in diagnosis switching and limited prognostic value for patients with an overlapping clinical phenotype. Future studies should attempt to stratify patients based not only on epilepsy syndrome diagnosis, but also on the presence of various electroclinical traits to more accurately predict outcome.

Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures

“…Although the most frequent seizure types in MAE are as expected (myoclonic atonic or atonic seizure, 100%; GTCS, 72.7%; and myoclonic seizures, 68.2%), 3,5,6,41 a minority of MAE patients have focal seizures, some (6.9%) with additional focal epileptiform activity on EEG. Focal EEG features have been reported in up to 39% of MAE cohorts 40 and have been proposed as a marker of poor prognosis in MAE 42 . However, we were not able to confirm this hypothesis in this cohort, as two of seven patients with focal EEG abnormalities achieved seizure remission, compared to 22 of 70 patients without focal abnormalities.…”

“…For example, antecedent neurodevelopmental impairments and autistic and cognitive deficits are more characteristic of DEE 43 . Moreover, Eschbach et al reported that more than one‐half of a cohort of 77 patients with suspected MAE undergo epilepsy diagnosis switching 40 . However, we believe that the MAE concept remains broadly useful to guide treatment and prognosis.…”

“…Ash1L is enriched in the brain in mice, and a role in epigenetic modification in brain functioning was implicated when in Ash1L knockout mice the activity‐dependent repression of neurexin 1α, a presynaptic adhesion molecule required for synaptic formation, was completely abolished 39 . CHD4 (chromodomain helicase DNA binding protein 4) is an adenosine triphosphate (ATP)‐dependent chromatin remodeler involved in epigenetic regulation of gene transcription, DNA repair, and cell cycle progression 40 . It is also a paralogue of CHD2 , which is associated with MAE 12 .…”

Clinical and genetic characteristics of patients with Doose syndrome

“…The ratio of patients who achieved seizure‐free status in previous studies has varied, with rates such as 32%, 58%, 67%, and 68%, in studies that used the original definition by Doose, 1,6,32,33 and 38% in studies in which the recent ILAE definition was applied 18 . Because we recruited patients with the aim of conducting gene analysis, it is possible that our study cohort included a higher number of patients with more severe or intractable conditions.…”

“…In this study, we used the original seizure semiology proposed by Doose to compare our cohort with those of previous studies. We included patients with tonic seizures or focal/multifocal EEG spikes because tonic seizures have been reported to develop late in the course of cases with an unfavorable outcome, 16,18 and multifocal EEG spikes have been observed in MAE patients 17,18 . We excluded patients with the following diagnoses: benign myoclonic epilepsy in infancy, Dravet syndrome, Lennox‐Gastaut syndrome, atypical childhood epilepsy with centrotemporal spikes, glucose transporter disorders, and progressive myoclonus epilepsies (https://www.epilepsydiagnosis.org).…”