Background: the field of epilepsies with a genetic aetiology is in continuous expansion, also thanks to the progress in genetic testing techniques and the introduction in clinical practice of array-CGH and NGS techniques, which allowed to get a better understanding on this matter. The identification of a genetic aetiology underlying a patient’s epilepsy has indeed important implications for both research and clinical practice. Rationale: we aimed at identifying risk factors associated to genetic epilepsies with respect to patients with no genetic diagnosis. Methods: in this retrospective, single-centre study we described the demographic and electro-clinical characteristics of a cohort of patients with genetic epilepsy or complex febrile seizures. We reviewed the medical charts of 447 patients with a diagnosis of epilepsy or febrile seizures followed in Fondazione I.R.C.C.S Policlinico San Matteo from 2013 to 2022; 181 patients were included in the study and were divided in group A, composed of 50 patients with positive genetic results, group B, composed of 117 patients with a negative genetic result, and group C, composed of 14 patients with a variant of unknown significance (VUS). Patients in group A were the object of the study and were compared for statistical purposes to patients in group B. Results: of the 50 patients who received a genetic diagnosis, 30 patients (60.0%) were males and 42 (84.0%) were of Caucasian ethnicity. 34 (68.0%) patients had a monogenic epilepsy, and variants in 30 different genes where identified, whereas in the remaining 16 patients (32.0%) it was possible to identify a chromosomal abnormality. Median age at seizure onset was 9 months, fifteen (30.0%) patients had a focal epilepsy, 18 (36.0%) patients had a generalized epilepsy, 8 (16.0%) patients had a combined generalized and focal epilepsy, 4 (8.0%) patients 2 had epileptic spasms and 5 (10.0%) had complex febrile seizures. In 12 (24.0%) patients, it was also possible to diagnose an epilepsy syndrome. Interictal EEG at onset was normal in 8 (16.0%) patients; 14 (28.0%) had focal slowing, 14 (28.0%) had generalized slowing, 27 (54.0%) had focal or multifocal spikes, 3 (6.0%) had generalized spikes. In six cases, ictal EEG was recorded: 3 (6.0%) patients had a focal ictal EEG and 3 (6.0%) patients had a generalized ictal EEG. Interictal EEG at last follow-up instead was normal in 14 (28.0%) patients; 5 (10.0%) patients had focal slowing, 11 (22.0%) patients had generalized slowing, 24 (48.0%) patients had focal or multifocal spikes, 3 (6.0%) patients had generalized spikes. In 3 (6.0%) cases, ictal EEG was recorded, and two patients had a focal ictal EEG, while one patient had a generalized ictal EEG. Compared to patients in the control group, patients with a genetic diagnosis were significantly younger at seizure onset, with a mean age at seizure onset of 29 months vs 60 months in the control group (p< .00001), and they exhibited significantly higher rates of drug-resistance (35.6% vs 20.0%; p= .037). Furthermore, in patients with a genetic diagnosis we observed a significantly higher rate of delayed development of motor abilities (78% vs 30%; p< .00001) and verbal abilities (80% vs 32%; p< .00001), as well as psychomotor delay/intellectual disability (90% vs 31%; p< .00001). Conclusions: our study offers an insight into the field of genetic epilepsy; we identified interesting distinctive features between patients with and without a genetic diagnosis. It is of great importance to continue to investigate and characterize such conditions, as well as to study and describe the long-term outcome of these patients.
Background: il campo delle epilessie genetiche è in continua crescita, grazie anche al progresso nell’ambito dei test genetici e all’introduzione, nella pratica clinica, dell’array-CGH e NGS, che ha consentito di aumentare le conoscenze in materia. Riconoscere l’eziologia genetica dell’epilessia di un paziente ha importanti implicazioni sia dal punto di vista clinico che della ricerca scientifica. Razionale: l’obiettivo dello studio era di identificare fattori di rischio per epilessia genetica rispetto a pazienti che non avessero una diagnosi genetica. Metodi: in questo studio retrospettivo, monocentrico, abbiamo descritto le caratteristiche demografiche ed elettrocliniche di una coorte di pazienti con diagnosi genetica di epilessia o crisi febbrili complesse. Abbiamo esaminato le cartelle cliniche di 447 pazienti afferenti alla Clinica Pediatrica della Fondazione I.R.C.C.S Policlinico San Matteo, che abbiano ricevuto una diagnosi di epilessia o crisi febbrili tra il 2013 e il 2022. 181 pazienti sono stati reclutati nello studio e sono stati divisi in tre gruppi: gruppo A, composto da 50 pazienti con una diagnosi genetica; gruppo B, composto da 117 pazienti con genetica negativa, e gruppo C, composto da 14 pazienti in cui sia stata identificata una variante di significato incerto (VUS). Ai fini statistici, i pazienti del gruppo A sono stati successivamente confrontati con i pazienti del gruppo B. Risultati: dei 50 pazienti che hanno ricevuto una diagnosi genetica, 30 (60.0%) erano maschi e 42 (84.0%) erano di etnia Caucasica. In particolare, 34 (68.0%) di essi avevano un’epilessia monogenica, e sono state riscontrate varianti patogeniche in 30 geni differenti. Nei restanti 16 (32.0%) pazienti sono state invece riscontrate anomalie cromosomiche. L’età mediana all’esordio è stata di 9 mesi; 15 (30.0%) pazienti hanno ricevuto diagnosi di epilessia focale, 18 (36.0%) pazienti hanno ricevuto diagnosi di epilessia generalizzata, 8 (16.0%) di epilessia combinata generalizzata e focale, 4 (8.0%) di spasmi epilettici e 5 (10.0%) di crisi febbrili complesse. In 12 (24.0%) pazienti è inoltre stato possibile formulare una diagnosi di sindrome epilettica. L’ EEG interictale all’esordio era normale in 8 (16.0%) pazienti; 14 (28.0%) pazienti avevano un rallentamento focale, 14 (28.0%) avevano un rallentamento generalizzato, 27 (54.0%) avevano punte focali o multifocali, 3 (6.0%) avevano punte generalizzate. In sei casi è stato registrato anche un EEG ictale: 3 (6.0%) pazienti avevano un EEG focale e 3 (6.0%) pazienti avevano un generalizzato. L'EEG all’ultima visita era normale in 14 (28.0%) pazienti; 5 (10.0%) pazienti avevano un rallentamento focale, 11 (22.0%) pazienti avevano un rallentamento generalizzato, 24 (48.0%) avevano punte focali o multifocali, 3 (6.0%) avevano punte generalizzate. In 3 (6.0%) casi è stato registrato anche un EEG ictale, focale in 2 pazienti e generalizzato nel terzo paziente. Rispetto ai pazienti del gruppo di controllo, i pazienti con diagnosi genetica erano significativamente più piccoli all’esordio delle crisi (età media di esordio di 29 mesi vs 60 mesi nel gruppo di controllo, p< .00001), e presentavano tassi più elevati di farmacoresistenza (35.6% vs 20.0%, p= .037). Inoltre, nei pazienti con diagnosi genetica abbiamo osservato un tasso significativamente più elevato di ritardo nell’acquisizione delle tappe motorie (78% vs 30%, p< .00001) e del linguaggio (80% vs 32%, p< .00001), nonché una maggiore incidenza di ritardo psicomotorio o disabilità intellettiva in tali pazienti (90% vs 31%, p< .00001). Conclusioni: il nostro studio offre delle informazioni utili per quanto concerne le epilessie genetiche; abbiamo identificato delle interessanti differenze tra i pazienti con e senza una diagnosi genetica. È di grande importanza continuare a fare ricerca e caratterizzare tali condizioni, nonché approfondire e descrivere gli esiti a lungo termine di tali pazienti.
Genetic epilepsies in childhood: demographic and electroclinical features of a cohort of patients followed in the paediatric clinic of Fondazione I.R.C.C.S. Policlinico San Matteo.
PRINCIPI, CELESTE
2022/2023
Abstract
Background: the field of epilepsies with a genetic aetiology is in continuous expansion, also thanks to the progress in genetic testing techniques and the introduction in clinical practice of array-CGH and NGS techniques, which allowed to get a better understanding on this matter. The identification of a genetic aetiology underlying a patient’s epilepsy has indeed important implications for both research and clinical practice. Rationale: we aimed at identifying risk factors associated to genetic epilepsies with respect to patients with no genetic diagnosis. Methods: in this retrospective, single-centre study we described the demographic and electro-clinical characteristics of a cohort of patients with genetic epilepsy or complex febrile seizures. We reviewed the medical charts of 447 patients with a diagnosis of epilepsy or febrile seizures followed in Fondazione I.R.C.C.S Policlinico San Matteo from 2013 to 2022; 181 patients were included in the study and were divided in group A, composed of 50 patients with positive genetic results, group B, composed of 117 patients with a negative genetic result, and group C, composed of 14 patients with a variant of unknown significance (VUS). Patients in group A were the object of the study and were compared for statistical purposes to patients in group B. Results: of the 50 patients who received a genetic diagnosis, 30 patients (60.0%) were males and 42 (84.0%) were of Caucasian ethnicity. 34 (68.0%) patients had a monogenic epilepsy, and variants in 30 different genes where identified, whereas in the remaining 16 patients (32.0%) it was possible to identify a chromosomal abnormality. Median age at seizure onset was 9 months, fifteen (30.0%) patients had a focal epilepsy, 18 (36.0%) patients had a generalized epilepsy, 8 (16.0%) patients had a combined generalized and focal epilepsy, 4 (8.0%) patients 2 had epileptic spasms and 5 (10.0%) had complex febrile seizures. In 12 (24.0%) patients, it was also possible to diagnose an epilepsy syndrome. Interictal EEG at onset was normal in 8 (16.0%) patients; 14 (28.0%) had focal slowing, 14 (28.0%) had generalized slowing, 27 (54.0%) had focal or multifocal spikes, 3 (6.0%) had generalized spikes. In six cases, ictal EEG was recorded: 3 (6.0%) patients had a focal ictal EEG and 3 (6.0%) patients had a generalized ictal EEG. Interictal EEG at last follow-up instead was normal in 14 (28.0%) patients; 5 (10.0%) patients had focal slowing, 11 (22.0%) patients had generalized slowing, 24 (48.0%) patients had focal or multifocal spikes, 3 (6.0%) patients had generalized spikes. In 3 (6.0%) cases, ictal EEG was recorded, and two patients had a focal ictal EEG, while one patient had a generalized ictal EEG. Compared to patients in the control group, patients with a genetic diagnosis were significantly younger at seizure onset, with a mean age at seizure onset of 29 months vs 60 months in the control group (p< .00001), and they exhibited significantly higher rates of drug-resistance (35.6% vs 20.0%; p= .037). Furthermore, in patients with a genetic diagnosis we observed a significantly higher rate of delayed development of motor abilities (78% vs 30%; p< .00001) and verbal abilities (80% vs 32%; p< .00001), as well as psychomotor delay/intellectual disability (90% vs 31%; p< .00001). Conclusions: our study offers an insight into the field of genetic epilepsy; we identified interesting distinctive features between patients with and without a genetic diagnosis. It is of great importance to continue to investigate and characterize such conditions, as well as to study and describe the long-term outcome of these patients.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/16019