Neuropediatrics 2015; 46 - PS02-12
DOI: 10.1055/s-0035-1550725

Unraveling the Genotype-Specific Response to Antiepileptic Medication in LIS1 Associated Classic Lissencephaly

S. Herbst 1, T. Geis 2, I. Borggräfe 3, O. Debus 4, M. Häußler 5, H. Phillipi 6, S. Ross 7, P. Vosschulte 8, U. Rossegg 9, N. Beaud 10, J. Budde 11, A. Hahn 12, G. Kurlemann 13, U. Hehr 1
  • 1Zentrum für Humangenetik, Universität Regensburg, Regensburg, Germany
  • 2Kinderklinik St. Hedwig, Klinik für Kinder- und Jugendmedizin, Regensburg, Germany
  • 3Kinderklinik im Dr. von Haunerschen Kinderspital, Kinderklinik der Universität München, München, Germany
  • 4Clemenshospital, Münster, Germany
  • 5Frühdiagnosezentrum, Universitätsklinikum Würzburg, Würzburg, Germany
  • 6SPZ Frankfurt Mitte, Frankfurt am Main, Germany
  • 7SPZ Erlangen, Univ. Kinder und Jugendklinik, Erlangen, Germany
  • 8Kinderarztpraxis, Münster, Germany
  • 9Landes- Frauen- und Kinderklinik Linz, Linz, Austria
  • 10Westküstenklinikum Heide, Klinik für Kinder- und Jugendmedizin, Heide, Germany
  • 11Klinik für Kinder- und Jugendmedizin, St Josefskrankenhaus, Freiburg, Germany
  • 12Zentrum für Kinderheilkunde und Jugendmedizin, Giessen, Germany
  • 13Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Münster, Münster, Germany

Aims: Patients with LIS1-associated classic lissencephaly typically present with severe and early psychomotor retardation in combination with an intractable seizure disorder. The aim of our study was to analyze the largest genotype-specific subgroup with regard to their response to antiepileptic therapy to develop LIS1-specific treatment recommendations.

Methods: Retrospective evaluation of 21 patients (age, 8 months–24 years) with genetically and radiologically confirmed LIS1-associated classic lissencephaly. Standardized neuropediatric assessment (n = 17) and/or family questionnaires (n = 20) were analyzed to study the genotype-specific response to antiepileptic medication and concomitant therapies in this homogenous cohort.

Results: All patients in our cohort showed pronounced developmental delay and a drug-resistant epilepsy. Overall, 86% of our cohort presented with their first seizure within the first 6 months of life. During the disease course, the majority suffered from multiple seizure types, generalized tonic–clonic seizures being the prominent type. Antiepileptic medication decreased the median number of daily seizures from 3.5/day to currently 1.0/day. Among the most commonly prescribed drugs, lamotrigine, valproate, and phenobarbital were rated the most successful anticonvulsant drugs with good or partial response rates for 84 to 100% of the patients. Lamotrigine was evaluated significantly better than oxcarbazepine, levetiracetam, and sultiame for which no treatment response was noted in 46 to 100% of the LIS1 cohort (p < 0.05).

In addition to pharmacological therapy, respiratory therapy, physiotherapy, and hippotherapy were rated as very effective concomitant therapies in > 80% of the LIS1 patients. In contrast, other commonly prescribed therapies such as speech therapy, early intervention programs, and aid to the blind were rated as ineffective or only partially effective in > 50% of the patients.

Conclusion: LIS1 mutations uniformly result in early drug-resistant epilepsy. Our preliminary data suggest that patients might benefit from LIS1-specific antiepileptic and concomitant therapy.

Keywords: lissencephaly, epilepsy, neuronal migrational disorder, genetics.