European Journal of Clinical Pharmacology

, Volume 75, Issue 5, pp 737–739 | Cite as

Use of a personalized phenytoin dosing approach to manage difficult to control seizures in an infant with a SCN2A mutation

  • Tatjana WelzelEmail author
  • Victoria C. Ziesenitz
  • Salome Waldvogel
  • Sabrina Scheidegger
  • Peter Weber
  • Johannes N. van den Anker
  • Verena Gotta
Letter to the Editor


The phenotype spectrum of sodium voltage-gated channel alpha subunit two (SCN2A) mutations expands. So far, gain-of-function mutations are associated with difficult-to-treat infantile-onset seizures, movement disorders or encephalopathies [1, 2, 3]. Phenytoin is one of few drugs effective in the treatment of SCN2A early-onset seizures [1, 2], but dosing due to its narrow therapeutic window is challenging. High phenytoin concentrations increase the risk of organ- and neurotoxicity (apoptosis, neuronal cell death) [4, 5] while at low concentrations seizure control may be lost. Uncontrolled seizures are life-threatening and associated with cerebral injury and developmental issues. Furthermore, phenytoin shows difficult dose-dependent interactions with other (anti-epileptic) drugs, increasing the risk for side-effects [6]. Dose adjustment tools have been developed for adults during steady-state conditions [7], but are lacking for infants, particularly when a quick seizure...


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Conflict of interest

The authors declare that they have no conflict of interest

Supplementary material

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  1. 1.
    Wolff M, Johannesen KM, Hedrich UBS, Masnada S, Rubboli G, Gardella E, Lesca G, Ville D, Milh M, Villard L, Afenjar A, Chantot-Bastaraud S, Mignot C, Lardennois C, Nava C, Schwarz N, Gérard M, Perrin L, Doummar D, Auvin S, Miranda MJ, Hempel M, Brilstra E, Knoers N, Verbeek N, van Kempen M, Braun KP, Mancini G, Biskup S, Hörtnagel K, Döcker M, Bast T, Loddenkemper T, Wong-Kisiel L, Baumeister FM, Fazeli W, Striano P, Dilena R, Fontana E, Zara F, Kurlemann G, Klepper J, Thoene JG, Arndt DH, Deconinck N, Schmitt-Mechelke T, Maier O, Muhle H, Wical B, Finetti C, Brückner R, Pietz J, Golla G, Jillella D, Linnet KM, Charles P, Moog U, Õiglane-Shlik E, Mantovani JF, Park K, Deprez M, Lederer D, Mary S, Scalais E, Selim L, van Coster R, Lagae L, Nikanorova M, Hjalgrim H, Korenke GC, Trivisano M, Specchio N, Ceulemans B, Dorn T, Helbig KL, Hardies K, Stamberger H, de Jonghe P, Weckhuysen S, Lemke JR, Krägeloh-Mann I, Helbig I, Kluger G, Lerche H, Møller RS (2017) Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders. Brain 140:1316–1336. CrossRefGoogle Scholar
  2. 2.
    Howell KB, McMahon JM, Carvill GL, Tambunan D, Mackay MT, Rodriguez-Casero V, Webster R, Clark D, Freeman JL, Calvert S, Olson HE, Mandelstam S, Poduri A, Mefford HC, Harvey AS, Scheffer IE (2015) SCN2A encephalopathy: a major cause of epilepsy of infancy with migrating focal seizures. Neurology 85:958–966. CrossRefGoogle Scholar
  3. 3.
    Sanders SJ, Campbell AJ, Cottrell JR, Moller RS, Wagner FF, Auldridge AL, Bernier RA, Catterall WA, Chung WK, Empfield JR, Georg AL Jr, Hipp JF, Khwaja O, Kiskinis E, Lal D, Malhotra D, Millichap JJ, Otis TS, Petrou S, Pitt G, Schust LF, Taylor CM, Tjernagel J, Spiro JE, Bender KJ (2018) Progress in understanding and treating SCN2A-mediated disorders. Trends Neurosci 41(7):442–456. CrossRefGoogle Scholar
  4. 4.
    Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, Dzietko M, Pesditschek S, Mai I, Dikranian K, Olney JW, Ikonomidou C (2002) Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 99(23):15089–15094. CrossRefGoogle Scholar
  5. 5.
    Forcelli PA, Kim J, Kondratyev A, Gale K (2011) Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia 52(12):e207–e211. CrossRefGoogle Scholar
  6. 6.
    Brigo F (2012) Phenytoin is dead, long live phenytoin? Epilepsy Behav 24(1):152. CrossRefGoogle Scholar
  7. 7.
    Vozeh S, Muir KT, Sheiner LB, Follath F (1981) Predicting individual phenytoin dosage. J Pharmacokinet Biopharm 9:131–146CrossRefGoogle Scholar
  8. 8.
    Winter ME, Tozer TN (2006) Phenytoin. In: Burton ME, Shaw LM, Schentag JJ, Evans WE (eds) Applied pharmacokinetics & pharmacodynamics principles of therapeutic drug monitoring, 4th edn. Lippincott Williams & Wilkins, Baltimore, pp 463–490Google Scholar
  9. 9.
    Loughnan PM, Greenwald A, Purton WW, Aranda JV, Watters G, Neims AH (1977) Pharmacokinetic observations of phenytoin disposition in the newborn and young infant. Arch Dis Child 52:302–309CrossRefGoogle Scholar
  10. 10.
    Guerrini R (2006) Epilepsy in children. Lancet 367(9509):499–524. CrossRefGoogle Scholar
  11. 11.
    Li-Wan-Po A, Girard T, Farndon P, Cooley C, Lithgow J (2010) Pharmacogenetics of CYP2C19: functional and clinical implications of a new variant CYP2C19*17. Br J Clin Pharmacol 69(3):222–230. CrossRefGoogle Scholar
  12. 12.
    Dodson WE (1988) Aspects of antiepileptic treatment in children. Epilepsia 29(Suppl 3):S10–S14CrossRefGoogle Scholar
  13. 13.
    Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE (2003) Developmental pharmacology-- drug disposition, action, and therapy in infants and children. N Engl J Med 349:1157–1167. CrossRefGoogle Scholar
  14. 14.
    Bourgeois BF, Dodson WE (1983) Phenytoin elimination in newborns. Neurology 33:173–178CrossRefGoogle Scholar
  15. 15.
    Yamamoto Y, Takahashi Y, Imai K, Miyakawa K, Ikeda H, Ueda Y, Yamaguchi T, Nasu H, Ohtani H, Shigematsu H, Kagawa Y, Inoue Y (2015) Individualized phenytoin therapy for Japanese pediatric patients with epilepsy based on CYP2C9 and CYP2C19 genotypes. Ther Drug Monit 37(2):229–235. CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Tatjana Welzel
    • 1
    • 2
    Email author
  • Victoria C. Ziesenitz
    • 1
    • 3
  • Salome Waldvogel
    • 3
  • Sabrina Scheidegger
    • 3
  • Peter Weber
    • 4
  • Johannes N. van den Anker
    • 1
    • 5
  • Verena Gotta
    • 1
  1. 1.Pediatric Pharmacology and Pharmacometrics, University Children’s Hospital Basel UKBBUniversity of BaselBaselSwitzerland
  2. 2.Pediatric Rheumatology, University Children’s Hospital Basel UKBBUniversity of BaselBaselSwitzerland
  3. 3.Department of Neonatology, University Children’s Hospital Basel UKBBUniversity of BaselBaselSwitzerland
  4. 4.Neuropediatrics and Developmental Medicine, University Children’s Hospital Basel UKBBUniversity of BaselBaselSwitzerland
  5. 5.Division of Clinical PharmacologyChildren’s National Health SystemWashingtonUSA

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