Copeptin as a serum biomarker of febrile seizures

Benjamin Stöcklin, Sotirios Fouzas, Paula Schillinger, Sevgi Cayir, Roswitha Skendaj, Michel Ramser, Peter Weber, Sven Wellmann, Benjamin Stöcklin, Sotirios Fouzas, Paula Schillinger, Sevgi Cayir, Roswitha Skendaj, Michel Ramser, Peter Weber, Sven Wellmann

Abstract

Background and objectives: Accurate diagnosis of febrile seizures in children presenting after paroxysmal episodes associated with fever, is hampered by the lack of objective postictal biomarkers. The aim of our study was to investigate whether FS are associated with increased levels of serum copeptin, a robust marker of arginine vasopressin secretion.

Methods: This was a prospective emergency-setting cross-sectional study of 161 children between six months and five years of age. Of these, 83 were diagnosed with febrile seizures, 69 had a febrile infection without seizures and nine had epileptic seizures not triggered by infection. Serum copeptin and prolactin levels were measured in addition to standard clinical, neurophysiological, and laboratory assessment.

Clinical trial registration: NCT01884766.

Results: Circulating copeptin was significantly higher in children with febrile seizures (median [interquartile range] 18.9 pmol/L [8.5-36.6]) compared to febrile controls (5.6 pmol/L [4.1-9.4]; p < 0.001), with no differences between febrile and epileptic seizures (21.4 pmol/L [16.1-46.6]; p = 0.728). In a multivariable regression model, seizures were the major determinant of serum copeptin (beta 0.509; p < 0.001), independently of clinical and baseline laboratory indices. The area under the receiver operating curve for copeptin was 0.824 (95% CI 0.753-0.881), significantly higher compared to prolactin (0.667 [0.585-0.742]; p < 0.001). The diagnostic accuracy of copeptin increased with decreasing time elapsed since the convulsive event (at 120 min: 0.879 [0.806-0.932] and at <60 min: 0.975 [0.913-0.997]).

Conclusions: Circulating copeptin has high diagnostic accuracy in febrile seizures and may be a useful adjunct for accurately diagnosing postictal states in the emergency setting.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1. Scatter dot plots of serum…
Fig 1. Scatter dot plots of serum copeptin and prolactin values in the three study groups.
Medians and interquartile ranges are also presented. Between-group comparisons were performed with Mann-Whitney U test. * Serum copeptin values in 4 cases (range 208–306 pmol/L) are outside the copeptin-axis limits of the graph. FS: febrile seizures; ES: epileptic seizures
Fig 2. Receiver operating characteristic curves of…
Fig 2. Receiver operating characteristic curves of serum copeptin and prolactin.
(A) In controls (n = 69) and in children with febrile seizures irrespectively to the time of presentation (n = 83); (B) In controls (n = 69) and in children with febrile seizures presented

References

    1. Fetveit A (2008) Assessment of febrile seizures in children. Eur J Pediatr 167: 17–27.
    1. Subcommittee on Febrile S, American Academy of P (2011) Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics 127: 389–394. 10.1542/peds.2010-3318
    1. Fein JA, Lavelle JM, Clancy RR (1997) Using age-appropriate prolactin levels to diagnose children with seizures in the emergency department. Acad Emerg Med 4: 202–205.
    1. Chen DK, So YT, Fisher RS, Therapeutics, Technology Assessment Subcommittee of the American Academy of N (2005) Use of serum prolactin in diagnosing epileptic seizures: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 65: 668–675.
    1. Veale WL, Cooper KE, Ruwe WD (1984) Vasopressin: its role in antipyresis and febrile convulsion. Brain Res Bull 12: 161–165.
    1. Landgraf R, Malkinson TJ, Veale WL, Lederis K, Pittman QJ (1990) Vasopressin and oxytocin in rat brain in response to prostaglandin fever. Am J Physiol 259: R1056–1062.
    1. Kasting NW, Veale WL, Cooper KE (1980) Convulsive and hypothermic effects of vasopressin in the brain of the rat. Can J Physiol Pharmacol 58: 316–319.
    1. Kasting NW, Veale WL, Cooper KE, Lederis K (1981) Vasopressin may mediate febrile convulsions. Brain Res 213: 327–333.
    1. Iwanaga M, Ohno M, Katoh A, Ohbuchi T, Ishikura T, Fujihara H, et al. (2011) Upregulation of arginine vasopressin synthesis in the rat hypothalamus after kainic acid-induced seizures. Brain Res 1424: 1–8. 10.1016/j.brainres.2011.09.030
    1. Ohno M, Fujihara H, Iwanaga M, Todoroki M, Katoh A, Ohbuchi T, et al. (2012) Induction of arginine vasopressin-enhanced green fluorescent protein expression in the locus coeruleus following kainic acid-induced seizures in rats. Stress 15: 435–442. 10.3109/10253890.2011.637185
    1. Aminoff MJ, Simon RP, Wiedemann E (1984) The hormonal responses to generalized tonic-clonic seizures. Brain 107 (Pt 2): 569–578.
    1. Kiviranta T, Tuomisto L, Jolkkonen J, Airaksinen EM (1996) Vasopressin in the cerebrospinal fluid of febrile children with or without seizures. Brain Dev 18: 110–113.
    1. Nickel CH, Bingisser R, Morgenthaler NG (2012) The role of copeptin as a diagnostic and prognostic biomarker for risk stratification in the emergency department. BMC Med 10: 7 10.1186/1741-7015-10-7
    1. Faul F, Erdfelder E, Lang AG, Buchner A (2007) G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods 39: 175–191.
    1. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. (2010) Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51: 676–685. 10.1111/j.1528-1167.2010.02522.x
    1. Schuchmann S, Schmitz D, Rivera C, Vanhatalo S, Salmen B, Mackie K, et al. (2006) Experimental febrile seizures are precipitated by a hyperthermia-induced respiratory alkalosis. Nat Med 12: 817–823.
    1. Schuchmann S, Hauck S, Henning S, Gruters-Kieslich A, Vanhatalo S, Schmitz D, et al. (2011) Respiratory alkalosis in children with febrile seizures. Epilepsia 52: 1949–1955. 10.1111/j.1528-1167.2011.03259.x
    1. Tolner EA, Hochman DW, Hassinen P, Otahal J, Gaily E, et al. (2011) Five percent CO(2) is a potent, fast-acting inhalation anticonvulsant. Epilepsia 52: 104–114. 10.1111/j.1528-1167.2010.02731.x
    1. L'Abate P, Wiegert S, Struck J, Wellmann S, Cannizzaro V (2013) Determinants of plasma copeptin: a systematic investigation in a pediatric mechanical ventilation model. Respir Physiol Neurobiol 185: 222–227. 10.1016/j.resp.2012.10.011
    1. Siesjo BK, von Hanwehr R, Nergelius G, Nevander G, Ingvar M (1985) Extra- and intracellular pH in the brain during seizures and in the recovery period following the arrest of seizure activity. J Cereb Blood Flow Metab 5: 47–57.
    1. Lagi A, Cuomo A, Veneziani F, Cencetti S (2013) Copeptin: a blood test marker of syncope. Int J Clin Pract 67: 512–515. 10.1111/ijcp.12123
    1. Katan M, Morgenthaler N, Widmer I, Puder JJ, Konig C, Müller B, et al. (2008) Copeptin, a stable peptide derived from the vasopressin precursor, correlates with the individual stress level. Neuro Endocrinol Lett 29: 341–346.
    1. Du JM, Sang G, Jiang CM, He XJ, Han Y (2013) Relationship between plasma copeptin levels and complications of community-acquired pneumonia in preschool children. Peptides 45: 61–65. 10.1016/j.peptides.2013.04.015
    1. Morgenthaler NG, Struck J, Alonso C, Bergmann A (2006) Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 52: 112–119.
    1. Burckhardt MA, Wellmann M, Fouzas S, Lapaire O, Burkhardt T, Benzing J, et al. (2014) Sexual disparity of copeptin in healthy newborn infants. J Clin Endocrinol Metab 99: E1750–1753. 10.1210/jc.2014-2244
    1. Rauchenzauner M, Haberlandt E, Foerster S, Ulmer H, Laimer M, Ebenbichler CF, et al. (2007) Brain-type natriuretic peptide secretion following febrile and afebrile seizures—a new marker in childhood epilepsy? Epilepsia 48: 101–106.
    1. Alehan F, Erol I, Cemil T, Bayraktar N, Ogus E, Tokel K. (2009) Elevated CK-MB mass and plasma brain-type natriuretic peptide concentrations following convulsive seizures in children and adolescents: possible evidence of subtle cardiac dysfunction. Epilepsia 50: 755–760. 10.1111/j.1528-1167.2008.01793.x
    1. Nevo I, Erlichman M, Algur N, Nir A (2011) N-terminal pro B-type natriuretic peptide levels in infants and children with acute non-cardiac diseases. Isr Med Assoc J 13: 420–424.
    1. Lee JH, Chan YH, Lai OF, Puthucheary J (2013) Vasopressin and copeptin levels in children with sepsis and septic shock. Intensive Care Med 39: 747–753. 10.1007/s00134-013-2825-z
    1. Pavlidou E, Hagel C, Panteliadis C (2013) Febrile seizures: recent developments and unanswered questions. Childs Nerv Syst 29: 2011–2017. 10.1007/s00381-013-2224-3
    1. Stroink H, van Donselaar CA, Geerts AT, Peters AC, Brouwer OF, Arts WF. (2003) The accuracy of the diagnosis of paroxysmal events in children. Neurology 60: 979–982.

Source: PubMed

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