Neuropediatrics 2019; 50(05): 294-299
DOI: 10.1055/s-0039-1693042
Original Article
Georg Thieme Verlag KG Stuttgart · New York

Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders and Parental Stress: Findings from a National, Prospective TSC Surveillance Study

1   Department of Pediatric Neurology, Saarland University Medical Center, Saarland Tuberous Sclerosis Complex Center, Homburg, Germany
,
Justine Hussong#
2   Department of Child and Adolescent Psychiatry, Saarland University Medical Center, Homburg, Germany
,
Marina Flotats-Bastardas
1   Department of Pediatric Neurology, Saarland University Medical Center, Saarland Tuberous Sclerosis Complex Center, Homburg, Germany
,
Darius Ebrahimi-Fakhari
3   Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
,
Michael Zemlin
1   Department of Pediatric Neurology, Saarland University Medical Center, Saarland Tuberous Sclerosis Complex Center, Homburg, Germany
,
Alexander von Gontard
2   Department of Child and Adolescent Psychiatry, Saarland University Medical Center, Homburg, Germany
,
Sascha Meyer#
1   Department of Pediatric Neurology, Saarland University Medical Center, Saarland Tuberous Sclerosis Complex Center, Homburg, Germany
› Author Affiliations
Funding This work was supported by the German Tuberous Sclerosis Foundation (Deutsche Tuberöse Sklerose Stiftung) (PNR 05/15) and Novartis (FPJ 0716), both to S. M. The authors confirm complete independence from the sponsors. The sponsors did not have any influence on either the content of the article or the conceptualization/design, methodology, investigation, supervision/oversight, data curation, and formal analysis of this study. The authors exclusively wrote this article. The study participants did not receive any compensation for their participation in the study.
Further Information

Publication History

30 March 2019

17 May 2019

Publication Date:
02 July 2019 (online)

Abstract

Aim To assess the role of the TAND (tuberous sclerosis complex [TSC] associated neuropsychiatric disorders) checklist as a screening tool for neuropsychiatric pathology, to evaluate behavioral and psychiatric symptoms and related parental stress in children with TSC, and to analyze associations between parental stress, TAND findings, and TSC pathology.

Method This is a prospective cohort study including 22 individuals from a national TSC surveillance study in Germany using demographic and clinical data, the TAND checklist, the Child Behavior Checklist (CBCL), and the Parenting Stress Index (PSI).

Results Mean (standard deviation) age at follow-up was 4 years (3 years 9 months), and 13/22 of patients were male. Seventeen children had epilepsy (focal: 9; generalized: 4; infantile spasms: 4). Developmental delay was diagnosed in 12/22 patients. The most prevalent TAND items were anxiety and mood swings in 10/22 children. At least one TAND item was reported by 17/22 patients, internalizing symptoms by 10/22, and externalizing symptoms by 11/22. In contrast, only one patient had a clinically relevant score in the CBCL scales. Of 22 parents, 12 reported clinically relevant parental stress due to both child and parenting factors. Higher total parental stress was associated with a higher TAND externalizing score (r = 0.49; p = 0.028) and TAND total score (r = 0.51; p = 0.016), a higher CBCL total score (r = 0.59; p = 0.005), and the number of antiepileptic drugs (r = 0.50; p = 0.017). Developmental delay was correlated with child stress factors (r = 0.48; p = 0.023).

Interpretation The TAND checklist appears to be a promising screening tool for neuropsychiatric problems in very young children with TSC. Parental stress in children with TSC is modified by TSC-related pathology, both neuropsychiatric and neurological.

Ethics Approval and Consent to Participate

The study was approved by the Institutional Review Board of Saarland, Germany (file no. 219/14). Patients or their guardians provided informed consent to their participating in the study including to publication of the results.


Authors’ Contributions

All authors made substantial contributions. Daniel Ebrahimi-Fakhari, Justine Hussong, and Sascha Meyer wrote the manuscript to which all coauthors contributed as well. Daniel Ebrahimi-Fakhari wrote the first draft of the manuscript, performed descriptive statistics, designed all tables, and contributed to conceptualization/design, methodology, investigation, data curation, and formal analysis and resources. Justine Hussong performed statistical analysis and contributed to formal analysis. Marina Flotats-Bastardas and, Darius Ebrahimi-Fakhari and Alexander von Gontard contributed to formal analysis and critical revision of the manuscript. Sascha Meyer was the chief investigator and contributed to conceptualization/design, methodology, investigation, supervision/oversight, funding acquisition, data curation, formal analysis, and resources. All authors read and approved the final manuscript.


# Daniel Ebrahimi-Fakhari, Justine Hussong, and Sascha Meyer contributed equally to this manuscript.


 
  • References

  • 1 Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008; 372 (9639): 657-668
  • 2 van Slegtenhorst M, de Hoogt R, Hermans C. , et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277 (5327): 805-808
  • 3 European Chromosome 16 Tuberous Sclerosis C. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75 (Suppl. 07) 1305-1315
  • 4 Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA. Tuberous sclerosis complex. Nat Rev Dis Primers 2016; 2: 16035
  • 5 Gómez MR. History of the tuberous sclerosis complex. Brain Dev 1995; 17 (Suppl): 55-57
  • 6 Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ. Molecular genetic advances in tuberous sclerosis. Hum Genet 2000; 107 (02) 97-114
  • 7 Lam HC, Nijmeh J, Henske EP. New developments in the genetics and pathogenesis of tumours in tuberous sclerosis complex. J Pathol 2017; 241 (02) 219-225
  • 8 Józwiak S, Schwartz RA, Janniger CK, Bielicka-Cymerman J. Usefulness of diagnostic criteria of tuberous sclerosis complex in pediatric patients. J Child Neurol 2000; 15 (10) 652-659
  • 9 Northrup H, Krueger DA. International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49: 243-254
  • 10 Krueger DA, Northrup H. ; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013; 49 (04) 255-265
  • 11 de Vries PJ, Whittemore VH, Leclezio L. , et al. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND Checklist. Pediatr Neurol 2015; 52 (01) 25-35
  • 12 Leclezio L, Jansen A, Whittemore VH, de Vries PJ. Pilot validation of the tuberous sclerosis-associated neuropsychiatric disorders (TAND) checklist. Pediatr Neurol 2015; 52 (01) 16-24
  • 13 de Vries PJ, Jansen A. Best use of the tuberous sclerosis complex-associated neuropsychiatric disorders (TAND) checklist. Dev Med Child Neurol 2019; 61 (02) 112-113
  • 14 Curatolo P, Moavero R, de Vries PJ. Neurological and neuropsychiatric aspects of tuberous sclerosis complex. Lancet Neurol 2015; 14 (07) 733-745
  • 15 de Vries PJ, Belousova E, Benedik MP. , et al; TOSCA Consortium and TOSCA Investigators. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J Rare Dis 2018; 13 (01) 157
  • 16 de Vries PJ, Wilde L, de Vries MC, Moavero R, Pearson DA, Curatolo P. A clinical update on tuberous sclerosis complex-associated neuropsychiatric disorders (TAND). Am J Med Genet C Semin Med Genet 2018; 178 (03) 309-320
  • 17 Waltereit R, Feucht M, de Vries MC, Huemer J, Roessner V, de Vries PJ. Neuropsychiatric manifestations in Tuberous Sclerosis Complex (TSC): diagnostic guidelines, TAND concept and therapy with mTOR inhibitors [in German]. Z Kinder Jugendpsychiatr Psychother 2019; 47 (02) 139-153
  • 18 Leclezio L, Gardner-Lubbe S, de Vries PJ. Is it feasible to identify natural clusters of TSC-associated neuropsychiatric disorders (TAND)?. Pediatr Neurol 2018; 81: 38-44
  • 19 Toldo I, Brasson V, Miscioscia M. , et al. Tuberous sclerosis-associated neuropsychiatric disorders: a paediatric cohort study. Dev Med Child Neurol 2019; 61 (02) 168-173
  • 20 Ebrahimi-Fakhari D, Mann LL, Poryo M. , et al. Incidence of tuberous sclerosis and age at first diagnosis: new data and emerging trends from a national, prospective surveillance study. Orphanet J Rare Dis 2018; 13 (01) 117
  • 21 Ebrahimi-Fakhari D, Zemlin M, Sauer H, Poryo M, Graf N, Meyer S. 25 years of ESPED as a surveillance tool for rare diseases in children in Germany: a critical analysis [in German]. Klin Padiatr 2018; 230 (04) 215-224
  • 22 Achenbach TM, Rescorla L. Manual for the ASEBA School-Age Forms & Profiles: An Integrated System of Multi-Informant Assessment. Burlington, VT: ASEBA; 2001
  • 23 Tröster H. Eltern-Belastungs-Inventar: EBI; deutsche Version des Parenting stress index (PSI) von R. R. Abidin. Göttingen, Bern: Hogrefe; 2011
  • 24 Kopp CM, Muzykewicz DA, Staley BA, Thiele EA, Pulsifer MB. Behavior problems in children with tuberous sclerosis complex and parental stress. Epilepsy Behav 2008; 13 (03) 505-510
  • 25 Gallagher A, Grant EP, Madan N, Jarrett DY, Lyczkowski DA, Thiele EA. MRI findings reveal three different types of tubers in patients with tuberous sclerosis complex. J Neurol 2010; 257 (08) 1373-1381
  • 26 Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol 2013; 125 (03) 317-332
  • 27 Bemister TB, Brooks BL, Dyck RH, Kirton A. Parent and family impact of raising a child with perinatal stroke. BMC Pediatr 2014; 14: 182
  • 28 Cappa KA, Begle AM, Conger JC, Dumas JE, Conger AJ. Bidirectional relationships between parenting stress and child coping competence: findings from the pace study. J Child Fam Stud 2011; 20 (03) 334-342
  • 29 Curatolo P, Napolioni V, Moavero R. Autism spectrum disorders in tuberous sclerosis: pathogenetic pathways and implications for treatment. J Child Neurol 2010; 25 (07) 873-880
  • 30 Factor RS, Swain DM, Scarpa A. Child autism spectrum disorder traits and parenting stress: the utility of using a physiological measure of parental stress. J Autism Dev Disord 2018; 48 (04) 1081-1091
  • 31 Backes M, Genç B, Schreck J, Doerfler W, Lehmkuhl G, von Gontard A. Cognitive and behavioral profile of fragile X boys: correlations to molecular data. Am J Med Genet 2000; 95 (02) 150-156