Turkiye Klinikleri Journal of Pediatrics

.: REVIEW
Epilepsili Çocuklarda Antinöbet İlaçların Bilişsel Fonksiyonlar Üzerine Etkileri: Sistematik Derleme
Anti-Seizure Medications in Children with Epilepsy Effects on Cognitive Functions: Systematic Review
Pınar ÖZKAN KARTa, Ali CANSUa
aKaradeniz Teknik Üniversitesi Tıp Fakültesi, Çocuk Nöroloji BD, Trabzon, Türkiye
Turkiye Klinikleri J Pediatr. 2023;32(1):42-55
doi: 10.5336/pediatr.2022-92208
Article Language: TR
Full Text
ÖZET
Bilişsel işlev bozukluğu, epilepsili hastalarda sıklıkla görülen komorbid hastalıklardan biridir. Bilişsel işlev bozukluğuna sahip hastaların yönetimi zordur ve bu hastaların yaşam kalitesinde sıklıkla bozulmaya yol açar. Bu durum, bazen nöbetlerin kendisinden daha yıpratıcı olabilir. Çoğunlukla bu bilişsel bozukluklar multifaktöriyeldir. Epilepsili hastalarda bilişsel bozukluğun nedeni tam olarak anlaşılamamış olsa da bilinen faktörler arasında altta yatan etiyolojik nedenler, nöbetlerin kendisi, ilaç tedavisinin yan etkileri ve psikososyokültürel sebepler yer alır. Bu sebeplerden dolayı antinöbet ilaçlar (ANİ), davranışsal ve bilişsel fonksiyonlara çoğunlukla olumsuz nadiren de olumlu şekilde önemli katkılarda bulunur. ANİ tedavisi sırasında gözlenen en yaygın santral sinir sistemi yan etkileri sedasyon, uyku hâli, dikkat dağınıklığı, uykusuzluk ve baş dönmesidir. Bilişsel yan etki riskini artıran en önemli faktörler ise çoklu ANİ kullanımı, yüksek ANİ dozu ve artan serum ilaç seviyeleridir. Olumsuz bilişsel etkiler, en düşük etkili doza yavaş titrasyonla ve politerapiden kaçınarak önlenebilir. Bu yüzden klinisyenler; hastaların ihtiyaçlarına göre en iyi bilişsel ve davranışsal profile sahip ANİ'leri seçip, uygun doz ve titrasyonla başlayarak ve nöropsikolojik testleri kullanarak bilişsel işlevi değerlendirip yan etkilere karşı uyanık olmalıdır. Nöropsikolojik izleme; epilepsili çocuklarda bireysel tıbbi bakımı iyileştirmek, öğrenme güçlüklerini ve sosyal sorunları önlemek için gereklidir. Bu derlemede, epilepsili çocuklarda klasik ve yeni kuşak ANİ'lerin bilişsel fonksiyonlar üzerine olan etkileri detaylı olarak değerlendirilecektir.

Anahtar Kelimeler: Antinöbet ilaçlar; epilepsi; bilişsel fonksiyonlar; çocuk
ABSTRACT
Cognitive dysfunction is one of the comorbid diseases frequently seen in patients with epilepsy. Patients with cognitive dysfunction are difficult to manage and often lead to deterioration in their quality of life. This can sometimes be more devastating than the seizures themselves. Often these cognitive impairments are multifactorial. Although the cause of cognitive impairment in patients with epilepsy is not fully understood, known factors include underlying etiological causes, seizures themselves, side effects of drug therapy, and psychosociocultural causes. For these reasons, anti-seizure medications make significant contributions to behavioral and cognitive functions, mostly negatively, but rarely positively. The most common central nervous system side effects observed during antiseizure medication therapy are sedation, drowsiness, distraction, insomnia, and dizziness. The most important factors that increase the risk of cognitive side effects are; multiple anti-seizure medication use, high anti-seizure medication dose, and increased serum drug levels. Adverse cognitive effects can be avoided by slow titration to the lowest effective dose and avoiding polytherapy. Therefore, clinicians should be alert to side effects by selecting anti-seizure medications with the best cognitive and behavioral profile according to their needs, starting with the appropriate dose and titration, and evaluating cognitive function using neuropsychological tests. Neuropsychological monitoring is necessary to improve individual medical care in children with epilepsy and to prevent learning difficulties and social problems. In this review, the effects of classical and new generation anti-seizure medications on cognitive functions will be evaluated in detail in children with epilepsy.

Keywords: Anti-seizures medications; epilepsy; cognitive functions; child
REFERENCES:
  1. Camfield P, Camfield C. Incidence, prevalence and aetiology of seizures and epilepsy in children. Epileptic Disord. 2015;17(2):117-23. [Crossref]  [PubMed] 
  2. Sankaraneni R, Lachhwani D. Antiepileptic drugs--a review. Pediatr Ann. 2015;44(2):e36-42. [Crossref]  [PubMed] 
  3. Cristofori I, Cohen-Zimerman S, Grafman J. Executive functions. Handb Clin Neurol. 2019;163:197-219. [Crossref]  [PubMed] 
  4. Haber SN. Corticostriatal circuitry. Dialogues Clin Neurosci. 2016;18(1):7-21. [Crossref]  [PubMed]  [PMC] 
  5. Kim EH, Ko TS. Cognitive impairment in childhood onset epilepsy: up-to-date information about its causes. Korean J Pediatr. 2016;59(4):155-64. [Crossref]  [PubMed]  [PMC] 
  6. Bourgeois BF. Determining the effects of antiepileptic drugs on cognitive function in pediatric patients with epilepsy. J Child Neurol. 2004;19 Suppl 1:S15-24. [Crossref]  [PubMed] 
  7. Mula M, Trimble MR. Antiepileptic drug-induced cognitive adverse effects: potential mechanisms and contributing factors. CNS Drugs. 2009;23(2):121-37. [Crossref]  [PubMed] 
  8. Reuner G, Kadish NE, Doering JH, Balke D, Schubert-Bast S. Attention and executive functions in the early course of pediatric epilepsy. Epilepsy Behav. 2016;60:42-9. [Crossref]  [PubMed] 
  9. Meador KJ. Cognitive and memory effects of the new antiepileptic drugs. Epilepsy Res. 2006;68(1):63-7. [Crossref]  [PubMed] 
  10. Katz I, Kim J, Gale K, Kondratyev A. Effects of lamotrigine alone and in combination with MK-801, phenobarbital, or phenytoin on cell death in the neonatal rat brain. J Pharmacol Exp Ther. 2007;322(2):494-500. [Crossref]  [PubMed] 
  11. Kim J, Kondratyev A, Gale K. Antiepileptic drug-induced neuronal cell death in the immature brain: effects of carbamazepine, topiramate, and levetiracetam as monotherapy versus polytherapy. J Pharmacol Exp Ther. 2007;323(1):165-73. [Crossref]  [PubMed] 
  12. Kim JS, Kondratyev A, Tomita Y, Gale K. Neurodevelopmental impact of antiepileptic drugs and seizures in the immature brain. Epilepsia. 2007;48 Suppl 5:19-26. Erratum in: Epilepsia. 2007;48(12):2379. [Crossref]  [PubMed] 
  13. Forcelli PA, Kim J, Kondratyev A, Gale K. Pattern of antiepileptic drug-induced cell death in limbic regions of the neonatal rat brain. Epilepsia. 2011;52(12):e207-11. [Crossref]  [PubMed]  [PMC] 
  14. Ulate-Campos A, Fernández IS. Cognitive and behavioral comorbidities: an unwanted effect of antiepileptic drugs in children. Semin Pediatr Neurol. 2017;24(4):320-30. [Crossref]  [PubMed] 
  15. Loring DW, Meador KJ. Cognitive side effects of antiepileptic drugs in children. Neurology. 2004;62(6):872-7. [Crossref]  [PubMed] 
  16. Bittigau P, Sifringer M, Ikonomidou C. Antiepileptic drugs and apoptosis in the developing brain. Ann N Y Acad Sci. 2003;993:103-14; discussion 123-4. [Crossref]  [PubMed] 
  17. Aldenkamp AP, Alpherts WC, Blennow G, Elmqvist D, Heijbel J, Nilsson HL, et al. Withdrawal of antiepileptic medication in children--effects on cognitive function: The Multicenter Holmfrid Study. Neurology. 1993;43(1):41-50. [Crossref]  [PubMed] 
  18. Schachter SC. Antiseizure drugs: mechanism of action, pharmacology, and adverse effects. Garcia P, ed. Up To Date: 2021. Erişim tarihi: 3 Mart 2022. [Link] 
  19. Hellstrom B, Barlach-Christoffersen M. Influence of phenobarbital on the psychomotor development and behaviour in preschool children with convulsions. Neuropadiatrie. 1980;11(2):151-60. [Crossref]  [PubMed] 
  20. Gallassi R, Morreale A, Di Sarro R, Marra M, Lugaresi E, Baruzzi A. Cognitive effects of antiepileptic drug discontinuation. Epilepsia. 1992;33 Suppl 6:S41-4. [PubMed] 
  21. Farwell JR, Lee YJ, Hirtz DG, Sulzbacher SI, Ellenberg JH, Nelson KB. Phenobarbital for febrile seizures--effects on intelligence and on seizure recurrence. N Engl J Med. 1990;322(6):364-9. Erratum in: N Engl J Med 1992;326(2):144. [Crossref]  [PubMed] 
  22. Stores G, Williams PL, Styles E, Zaiwalla Z. Psychological effects of sodium valproate and carbamazepine in epilepsy. Arch Dis Child. 1992;67(11):1330-7. [Crossref]  [PubMed]  [PMC] 
  23. Trimble MR. Anticonvulsant drugs and cognitive function: a review of the literature. Epilepsia. 1987;28 Suppl 3:S37-45. [Crossref]  [PubMed] 
  24. Xiao F, Caciagli L, Wandschneider B, Sander JW, Sidhu M, Winston G, et al. Effects of carbamazepine and lamotrigine on functional magnetic resonance imaging cognitive networks. Epilepsia. 2018;59(7):1362-71. [Crossref]  [PubMed]  [PMC] 
  25. Riva D, Devoti M. Carbamazepine withdrawal in children with previous symptomatic partial epilepsy: effects on neuropsychologic function. J Child Neurol. 1999;14(6):357-62. [Crossref]  [PubMed] 
  26. O'Dougherty M, Wright FS, Cox S, Walson P. Carbamazepine plasma concentration. Relationship to cognitive impairment. Arch Neurol. 1987;44(8):863-7. [Crossref]  [PubMed] 
  27. Aman MG, Werry JS, Paxton JW, Turbott SH, Stewart AW. Effects of carbamazepine on psychomotor performance in children as a function of drug concentration, seizure type, and time of medication. Epilepsia. 1990;31(1):51-60. [Crossref]  [PubMed] 
  28. Berg I, Butler A, Ellis M, Foster J. Psychiatric aspects of epilepsy in childhood treated with carbamazepine, phenytoin or sodium valproate: a random trial. Dev Med Child Neurol. 1993;35(2):149-57. [Crossref]  [PubMed] 
  29. Herranz JL, Arteaga R, Armijo JA. Side effects of sodium valproate in monotherapy controlled by plasma levels: a study in 88 pediatric patients. Epilepsia. 1982;23(2):203-14. [Crossref]  [PubMed] 
  30. Masur D, Shinnar S, Cnaan A, Shinnar RC, Clark P, Wang J, et al; Childhood Absence Epilepsy Study Group. Pretreatment cognitive deficits and treatment effects on attention in childhood absence epilepsy. Neurology. 2013;81(18):1572-80. [Crossref]  [PubMed]  [PMC] 
  31. Camposano SE, Major P, Halpern E, Thiele EA. Vigabatrin in the treatment of childhood epilepsy: a retrospective chart review of efficacy and safety profile. Epilepsia. 2008;49(7):1186-91. [Crossref]  [PubMed] 
  32. Eun SH, Kim HD, Chung HJ, Kang HC, Lee JS, Kim JS, et al. A multicenter trial of oxcarbazepine oral suspension monotherapy in children newly diagnosed with partial seizures: a clinical and cognitive evaluation. Seizure. 2012;21(9):679-84. [Crossref]  [PubMed] 
  33. Tzitiridou M, Panou T, Ramantani G, Kambas A, Spyroglou K, Panteliadis C. Oxcarbazepine monotherapy in benign childhood epilepsy with centrotemporal spikes: a clinical and cognitive evaluation. Epilepsy Behav. 2005;7(3):458-67. [Crossref]  [PubMed] 
  34. Pressler RM, Binnie CD, Coleshill SG, Chorley GA, Robinson RO. Effect of lamotrigine on cognition in children with epilepsy. Neurology. 2006;66(10):1495-9. [Crossref]  [PubMed] 
  35. Franz DN, Tudor C, Leonard J, Egelhoff JC, Byars A, Valerius K, et al. Lamotrigine therapy of epilepsy in tuberous sclerosis. Epilepsia. 2001;42(7):935-40. [Crossref]  [PubMed] 
  36. Uvebrant P, Bauzienè R. Intractable epilepsy in children. The efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics. 1994;25(6):284-9. [Crossref]  [PubMed] 
  37. Brodbeck V, Jansen V, Fietzek U, Muehe C, Weber G, Heinen F. Long-term profile of lamotrigine in 119 children with epilepsy. Eur J Paediatr Neurol. 2006;10(3):135-41. [Crossref]  [PubMed] 
  38. Lee DO, Steingard RJ, Cesena M, Helmers SL, Riviello JJ, Mikati MA. Behavioral side effects of gabapentin in children. Epilepsia. 1996;37(1):87-90. [Crossref]  [PubMed] 
  39. Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Nichols ME, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia. 1999;40(9):1279-85. [Crossref]  [PubMed] 
  40. Kälviäinen R, Aikiä M, Mervaala E, Saukkonen AM, Pitkänen A, Riekkinen PJ Sr. Long-term cognitive and EEG effects of tiagabine in drug-resistant partial epilepsy. Epilepsy Res. 1996;25(3):291-7. [Crossref]  [PubMed] 
  41. Dodrill CB, Arnett JL, Deaton R, Lenz GT, Sommerville KW. Tiagabine versus phenytoin and carbamazepine as add-on therapies: effects on abilities, adjustment, and mood. Epilepsy Res. 2000;42(2-3):123-32. [Crossref]  [PubMed] 
  42. Burton LA, Harden C. Effect of topiramate on attention. Epilepsy Res. 1997;27(1):29-32. [Crossref]  [PubMed] 
  43. Thompson PJ, Baxendale SA, Duncan JS, Sander JW. Effects of topiramate on cognitive function. J Neurol Neurosurg Psychiatry. 2000;69(5):636-41. [Crossref]  [PubMed]  [PMC] 
  44. Aldenkamp AP, Baker G, Mulder OG, Chadwick D, Cooper P, Doelman J, et al. A multicenter, randomized clinical study to evaluate the effect on cognitive function of topiramate compared with valproate as add-on therapy to carbamazepine in patients with partial-onset seizures. Epilepsia. 2000;41(9):1167-78. [Crossref]  [PubMed] 
  45. Dooley JM, Camfield PR, Smith E, Langevin P, Ronen G. Topiramate in intractable childhood onset epilepsy--a cautionary note. Can J Neurol Sci. 1999;26(4):271-3. [Crossref]  [PubMed] 
  46. Coppola G, Verrotti A, Resicato G, Ferrarelli S, Auricchio G, Operto FF, et al. Topiramate in children and adolescents with epilepsy and mental retardation: a prospective study on behavior and cognitive effects. Epilepsy Behav. 2008;12(2):253-6. [Crossref]  [PubMed] 
  47. Gerber PE, Hamiwka L, Connolly MB, Farrell K. Factors associated with behavioral and cognitive abnormalities in children receiving topiramate. Pediatr Neurol. 2000;22(3):200-3. [Crossref]  [PubMed] 
  48. Lagae L. The importance of assessing behaviour and cognition in antiepileptic drug trials in children and adolescents. Acta Neurol Belg. 2017;117(2):425-32. [Crossref]  [PubMed] 
  49. Hanci F, Canpolat M, Per H, Gumus H, Kumandas S. The relation between antiepileptic drug type and cognitive functions in childhood epilepsy: a prospective observational study. Experimental Biomedical Research. 2019;2(2):62-8. [Crossref] 
  50. Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and mono-therapy trial. Seizure. 2005;14(1):66-71. [Crossref]  [PubMed] 
  51. Levisohn PM, Mintz M, Hunter SJ, Yang H, Jones J; N01103 Levetiracetam Study Group. Neurocognitive effects of adjunctive levetiracetam in children with partial-onset seizures: a randomized, double-blind, placebo-controlled, noninferiority trial. Epilepsia. 2009;50(11):2377-89. [Crossref]  [PubMed] 
  52. Major P, Greenberg E, Khan A, Thiele EA. Pyridoxine supplementation for the treatment of levetiracetam-induced behavior side effects in children: preliminary results. Epilepsy Behav. 2008;13(3):557-9. [Crossref]  [PubMed] 
  53. Berent S, Sackellares JC, Giordani B, Wagner JG, Donofrio PD, Abou-Khalil B. Zonisamide (CI-912) and cognition: results from preliminary study. Epilepsia. 1987;28(1):61-7. [Crossref]  [PubMed] 
  54. Eun SH, Kim HD, Eun BL, Lee IK, Chung HJ, Kim JS, et al. Comparative trial of low- and high-dose zonisamide as monotherapy for childhood epilepsy. Seizure. 2011;20(7):558-63. [Crossref]  [PubMed] 
  55. Bawden HN, Camfield CS, Camfield PR, Cunningham C, Darwish H, Dooley JM, et al. The cognitive and behavioural effects of clobazam and standard monotherapy are comparable. Canadian Study Group for Childhood Epilepsy. Epilepsy Res. 1999;33(2-3):133-43. [Crossref]  [PubMed] 
  56. Andrade R, García-Espinosa A, Machado-Rojas A, García-González ME, Trápaga-Quincoses O, Morales-Chacón LM. Estudio prospectivo, abierto, controlado y aleatorizado de clobazam frente a carbamacepina en pacientes con crisis frecuentes de epilepsia rolándica [A prospective, open, controlled and randomised study of clobazam versus carbamazepine in patients with frequent episodes of Rolandic epilepsy]. Rev Neurol. 2009;49(11):581-6. Spanish. [Crossref]  [PubMed] 
  57. Grosso S, Coppola G, Dontin SD, Gobbi G, Pruna D, Accorsi P, et al. Efficacy and safety of rufinamide in children under four years of age with drug-resistant epilepsies. Eur J Paediatr Neurol. 2014;18(5):641-5. doi: 10.1016/j.ejpn.2014.05.001. Erratum in: Eur J Paediatr Neurol. 2015;19(3):388. [Crossref]  [PubMed] 
  58. Thome-Souza S, Kadish NE, Ramgopal S, Sánchez Fernández I, Bergin AM, Bolton J, et al. Safety and retention rate of rufinamide in 300 patients: a single pediatric epilepsy center experience. Epilepsia. 2014;55(8):1235-44. [Crossref]  [PubMed] 
  59. Meador KJ, Yang H, Pi-a-Garza JE, Laurenza A, Kumar D, Wesnes KA. Cognitive effects of adjunctive perampanel for partial-onset seizures: A randomized trial. Epilepsia. 2016;57(2):243-51. [Crossref]  [PubMed]  [PMC] 
  60. De Liso P, Vigevano F, Specchio N, De Palma L, Bonanni P, Osanni E, et al. Effectiveness and tolerability of perampanel in children and adolescents with refractory epilepsies-An Italian observational multicenter study. Epilepsy Res. 2016;127:93-100. [Crossref]  [PubMed] 
  61. Salinsky M, Storzbach D, Munoz S. Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial. Neurology. 2010;74(9):755-61. [Crossref]  [PubMed] 
  62. IJff DM, van Veenendaal TM, Debeij-van Hall MH, Jansen JF, de Louw AJ, Majoie MH, et al. The cognitive profile of ethosuximide in children. Paediatr Drugs. 2016;18(5):379-85. [Crossref]  [PubMed] 
  63. Nabbout R, Mistry A, Zuberi S, Villeneuve N, Gil-Nagel A, Sanchez-Carpintero R, et al; FAiRE, DS Study Group. Fenfluramine for treatment-resistant seizures in patients with dravet syndrome receiving stiripentol-inclusive regimens: a randomized clinical trial. JAMA Neurol. 2020;77(3):300-8. [Crossref]  [PubMed]  [PMC] 
  64. Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, et al; FAiRE DS Study Group. Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomised, double-blind, placebo-controlled trial. Lancet. 2019;394(10216):2243-54. [Crossref]  [PubMed] 
  65. Gay PE, Mecham GF, Coskey JS, Sadler T, Thompson JA. Behavioral effects of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). Psychol Rep. 1995;77(3 Pt 2):1208-10. [Crossref]  [PubMed] 
  66. Thompson MD, Martin RC, Grayson LP, Ampah SB, Cutter G, Szaflarski JP, et al. Cognitive function and adaptive skills after a one-year trial of cannabidiol (CBD) in a pediatric sample with treatment-resistant epilepsy. Epilepsy Behav. 2020;111:107299. [Crossref]  [PubMed] 
  67. Miller I, Scheffer IE, Gunning B, Sanchez-Carpintero R, Gil-Nagel A, Perry MS, et al; GWPCARE2 Study Group. Dose-ranging effect of adjunctive oral cannabidiol vs placebo on convulsive seizure frequency in dravet syndrome: a randomized clinical trial. JAMA Neurol. 2020;77(5):613-21. Erratum in: JAMA Neurol. 2020;77(5):655. [Crossref]  [PubMed]  [PMC] 
  68. Metternich B, Wagner K, Geiger MJ, Hirsch M, Schulze-Bonhage A, Klotz KA. Cognitive and behavioral effects of cannabidiol in patients with treatment-resistant epilepsy. Epilepsy Behav. 2021;114(Pt A):107558. [Crossref]  [PubMed] 
  69. Gaston TE, Martin RC, Szaflarski JP. Cannabidiol (CBD) and cognition in epilepsy. Epilepsy Behav. 2021;124:108316. [Crossref]  [PubMed] 
  70. Besag FMC, Vasey MJ. Neurocognitive effects of antiseizure medications in children and adolescents with epilepsy. Paediatr Drugs. 2021;23(3):253-86. [Crossref]  [PubMed] 
  71. Meador KJ, Gevins A, Leese PT, Otoul C, Loring DW. Neurocognitive effects of brivaracetam, levetiracetam, and lorazepam. Epilepsia. 2011;52(2):264-72. [Crossref]  [PubMed] 
  72. Ben-Zeev B, Watemberg N, Lerman P, Barash I, Brand N, Lerman-Sagie T. Sulthiame in childhood epilepsy. Pediatr Int. 2004;46(5):521-4. [Crossref]  [PubMed] 
  73. Wirrell E, Sherman EM, Vanmastrigt R, Hamiwka L. Deterioration in cognitive function in children with benign epilepsy of childhood with central temporal spikes treated with sulthiame. J Child Neurol. 2008;23(1):14-21. [Crossref]  [PubMed] 
  74. Tacke M, Gerstl L, Heinen F, Heukaeufer I, Bonfert M, Bast T, et al; German HEAD Study group. Effect of anticonvulsive treatment on neuropsychological performance in children with BECTS. Eur J Paediatr Neurol. 2016;20(6):874-9. [PubMed] 
  75. Topçu Y, Kılıç B, Tekin HG, Aydın K, Turanlı G. Effects of sulthiame on seizure frequency and EEG in children with electrical status epilepticus during slow sleep. Epilepsy Behav. 2021;116:107793. [Crossref]  [PubMed] 

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4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com