Characterization of the Epileptogenic Phenotype and Response to Antiseizure Medications in Lissencephaly Patients

Abstract

Background Patients with lissencephaly typically present with severe psychomotor retardation and drug-resistant seizures. The aim of this study was to characterize the epileptic phenotype in a genotypically and radiologically well-defined patient cohort and to evaluate the response to antiseizure medication (ASM). Therefore, we retrospectively evaluated 47 patients of five genetic forms (LIS1/PAFAH1B1, DCX, DYNC1H1, TUBA1A, TUBG1) using family questionnaires, standardized neuropediatric assessments, and patients' medical reports.

Results All but two patients were diagnosed with epilepsy. Median age at seizure onset was 6 months (range: 2.1–42.0), starting with epileptic spasms in 70%. Standard treatment protocols with hormonal therapy (ACTH or corticosteroids) and/or vigabatrin were the most effective approach for epileptic spasms, leading to seizure control in 47%. Seizures later in the disease course were most effectively treated with valproic acid and lamotrigine, followed by vigabatrin and phenobarbital, resulting in seizure freedom in 20%. Regarding psychomotor development, lissencephaly patients presenting without epileptic spasms were significantly more likely to reach various developmental milestones compared to patients with spasms.

Conclusion Classic lissencephaly is highly associated with drug-resistant epilepsy starting with epileptic spasms in most patients. The standard treatment protocols for infantile epileptic spasms syndrome lead to freedom from seizures in around half of the patients. Due to the association of epileptic spasms with an unfavorable course of psychomotor development, early and reliable diagnosis and treatment of spasms should be pursued. For epilepsies occurring later in childhood, ASM with valproic acid and lamotrigine, followed by vigabatrin and phenobarbital, appears to be most effective.

Keywords

lissencephaly - neuronal migration - antiseizure medication - LIS1/PAFAH1B1 - DCX - epileptic spasms

^* These authors contributed equally to the article.

Publikationsverlauf

Eingereicht: 27. Januar 2024

Angenommen: 26. Juli 2024

Artikel online veröffentlicht:
30. August 2024

• References

• 1 Brock S, Dobyns WB, Jansen A. PAFAH1B1-related lissencephaly/subcortical band heterotopia. In: Adam MP, Feldman J, Mirzaa GM. et al., eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2009: 1993-2024
• 2 Dobyns WB, Stratton RF, Parke JT, Greenberg F, Nussbaum RL, Ledbetter DH. Miller-Dieker syndrome: lissencephaly and monosomy 17p. J Pediatr 1983; 102 (04) 552-558
• 3 Koenig M, Dobyns WB, Di Donato N. Lissencephaly: update on diagnostics and clinical management. Eur J Paediatr Neurol 2021; 35: 147-152
• 4 Di Donato N, Chiari S, Mirzaa GM. et al. Lissencephaly: expanded imaging and clinical classification. Am J Med Genet A 2017; 173 (06) 1473-1488
• 5 Dobyns WB. The clinical patterns and molecular genetics of lissencephaly and subcortical band heterotopia. Epilepsia 2010; 51 (Suppl. 01) 5-9
• 6 Herbst SM, Proepper CR, Geis T. et al. LIS1/PAFAH1B1-associated classic lissencephaly: a retrospective, multicenter survey of the epileptogenic phenotype and response to antiepileptic drugs. Brain Dev 2016; 38 (04) 399-406
• 7 Kolbjer S, Martin DA, Pettersson M, Dahlin M, Anderlid B-M. Lissencephaly in an epilepsy cohort: molecular, radiological and clinical aspects. Eur J Paediatr Neurol 2021; 30: 71-81
• 8 Brockmann K. Acquisition of rare neurological disorders in childhood (Erhebung Seltener Neurologischer Erkrankungen im Kindesalter). Neuropediatrics 2014; 45 (S0 1): fp036
• 9 Brandstetter S, Toncheva AA, Niggel J. et al. KUNO-Kids study group. KUNO-Kids birth cohort study: rationale, design, and cohort description. Mol Cell Pediatr 2019; 6 (01) 1
• 10 Borozdin W, Boehm D, Leipoldt M. et al. SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet 2004; 41 (09) e113
• 11 Bender R, Lange S. Adjusting for multiple testing–when and how?. J Clin Epidemiol 2001; 54 (04) 343-349
• 12 des Portes V, Francis F, Pinard JM. et al. doublecortin is the major gene causing X-linked subcortical laminar heterotopia (SCLH). Hum Mol Genet 1998; 7 (07) 1063-1070
• 13 des Portes V, Pinard JM, Billuart P. et al. A novel CNS gene required for neuronal migration and involved in X-linked subcortical laminar heterotopia and lissencephaly syndrome. Cell 1998; 92 (01) 51-61
• 14 Di Donato N, Timms AE, Aldinger KA. et al. University of Washington Center for Mendelian Genomics. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly. Genet Med 2018; 20 (11) 1354-1364
• 15 Chiba E, Kimura Y, Shimizu-Motohashi Y. et al. Clinical and neuroimaging findings in patients with lissencephaly/subcortical band heterotopia spectrum: a magnetic resonance conventional and diffusion tensor study. Neuroradiology 2022; 64 (04) 825-836
• 16 Moeller JJ, Rahey SR, Sadler RM. Lamotrigine-valproic acid combination therapy for medically refractory epilepsy. Epilepsia 2009; 50 (03) 475-479
• 17 Beran RG, Berkovic SF, Dunagan FM. et al. Double-blind, placebo-controlled, crossover study of lamotrigine in treatment-resistant generalised epilepsy. Epilepsia 1998; 39 (12) 1329-1333
• 18 Pisani F, Oteri G, Russo MF, Di Perri R, Perucca E, Richens A. The efficacy of valproate-lamotrigine comedication in refractory complex partial seizures: evidence for a pharmacodynamic interaction. Epilepsia 1999; 40 (08) 1141-1146
• 19 Ramantani G, Bölsterli BK, Alber M. et al. Treatment of infantile spasm syndrome: update from the interdisciplinary guideline committee coordinated by the German-Speaking Society of Neuropediatrics. Neuropediatrics 2022; 53 (06) 389-401
• 20 Knupp KG, Coryell J, Nickels KC. et al. Pediatric Epilepsy Research Consortium. Response to treatment in a prospective national infantile spasms cohort. Ann Neurol 2016; 79 (03) 475-484
• 21 Guang S, Mao L, Zhong L. et al. Hormonal therapy for infantile spasms: a systematic review and meta-analysis. Front Neurol 2022; 13: 772333
• 22 Gesellschaft für Neuropädiatrie. Therapie der Blitz-Nick-Salaam Epilepsie (West-Syndrom). Accessed July 31 2024 at: https://www.awmf.org/leitlinien/detail/ll/022-022.html
• 23 Go CY, Mackay MT, Weiss SK. et al. Evidence-based guideline update medical treatment of infantile spasms: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2012; 78 (24) 1974-1980