Skip to main content

Advertisement

SpringerLink
Log in

The longitudinal evolution of cerebral blood flow in children with tuberous sclerosis assessed by arterial spin labeling magnetic resonance imaging may be related to cognitive performance

  • Neuro
  • Published:
European Radiology Aims and scope Submit manuscript

Abstract

Objective

To study longitudinal changes in tuber and whole-brain perfusion in children with tuberous sclerosis complex (TSC) using arterial spin labeling (ASL) perfusion MRI and correlate them with pathological EEG slow wave activity and neurodevelopmental outcomes.

Methods

Retrospective longitudinal cohort study of 13 children with TSC, 3 to 6 serial ASL-MRI scans between 2 months and 7 years of age (53 scans in total), and an EEG examination performed within 2 months of the last MRI. Tuber cerebral blood flow (CBF) values were calculated in tuber segmentation masks, and tuber:cortical CBF ratios were used to study tuber perfusion. Logistic regression analysis was performed to identify which initial tuber characteristics (CBF value, volume, location) in the first MRI predicted tubers subsequently associated with EEG slow waves. Whole-brain and lobar CBF values were extracted for all patient scans and age-matched controls. CBF ratios were compared in patients and controls to study longitudinal changes in whole-brain CBF.

Results

Perfusion was reduced in tubers associated with EEG slow waves compared with other tubers. Low tuber CBF values around 6 months of age and large tuber volumes were predictive of tubers subsequently associated with EEG slow waves. Patients with severe developmental delay had more severe whole-brain hypoperfusion than those with no/mild delay, which became apparent after 2 years of age and were not associated with a higher tuber load.

Conclusions

Dynamic changes in tuber and brain perfusion occur over time. Perfusion is significantly reduced in tubers associated with EEG slow waves. Whole-brain perfusion is significantly reduced in patients with severe delay.

Key Points

• Tubers associated with EEG slow wave activity were significantly more hypoperfused than other tubers, especially after 1 year of age.

• Larger and more hypoperfused tubers at 6 months of age were more likely to subsequently be associated with pathological EEG slow wave activity.

• Patients with severe developmental delay had more extensive and severe global hypoperfusion than those without developmental delay.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

ASD:

Autism spectrum disorder

ASL:

Arterial spin labeling

CBF:

Cerebral blood flow

IQR:

Interquartile range

PET:

Positron emission tomography

ROC:

Receiver operating characteristics

SPECT:

Single-photon emission computed tomography

SPM:

Statistical parametric mapping

TSC:

Tuberous sclerosis complex

References

  1. Mühlebner A, van Scheppingen J, Hulshof HM et al (2016) Novel histopathological patterns in cortical tubers of epilepsy surgery patients with tuberous sclerosis complex. PLoS One 11:e0157396–e0157396. https://doi.org/10.1371/journal.pone.0157396

    Article  CAS  Google Scholar 

  2. Peters JM, Taquet M, Prohl AK et al (2013) Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions. Future Neurol 8:583–597. https://doi.org/10.2217/fnl.13.37

    Article  CAS  Google Scholar 

  3. Gupta A, de Bruyn G, Tousseyn S et al (2020) Epilepsy and neurodevelopmental comorbidities in tuberous sclerosis complex: a natural history study. Pediatr Neurol 106:10–16. https://doi.org/10.1016/j.pediatrneurol.2019.12.016

    Article  Google Scholar 

  4. Nabbout R, Belousova E, Benedik MP et al (2018) Epilepsy in tuberous sclerosis complex: findings from the TOSCA Study. Epilepsia Open 4:73–84. https://doi.org/10.1002/epi4.12286

    Article  Google Scholar 

  5. Kaczorowska M, Jurkiewicz E, Domańska-Pakieła D et al (2011) Cerebral tuber count and its impact on mental outcome of patients with tuberous sclerosis complex. Epilepsia 52:22–27. https://doi.org/10.1111/j.1528-1167.2010.02892.x

    Article  Google Scholar 

  6. Bolton PF, Park RJ, Higgins JNP et al (2002) Neuro-epileptic determinants of autism spectrum disorders in tuberous sclerosis complex. Brain 125:1247–1255. https://doi.org/10.1093/brain/awf124

    Article  Google Scholar 

  7. Numis AL, Major P, Montenegro MA et al (2011) Identification of risk factors for autism spectrum disorders in tuberous sclerosis complex. Neurology 76:981–987. https://doi.org/10.1212/WNL.0b013e3182104347

    Article  CAS  Google Scholar 

  8. Doherty C, Goh S, Poussaint TY et al (2005) Prognostic significance of tuber count and location in tuberous sclerosis complex. J Child Neurol 20:837–841. https://doi.org/10.1177/08830738050200101301

    Article  Google Scholar 

  9. Okanishi T, Fujimoto A, Kanai S et al (2020) Association between diffuse cerebral MRI lesions and the occurrence and intractableness of West syndrome in tuberous sclerosis complex. Epilepsy Behav 103:106535. https://doi.org/10.1016/j.yebeh.2019.106535

    Article  Google Scholar 

  10. El-Beheiry A, Nassef H, Darwish R et al (2018) Which cortical tuber type is more epileptogenic? Magnetic resonance imaging-based study in children with tuberous sclerosis complex. Alexandria J Pediatr 31:43. https://doi.org/10.4103/AJOP.AJOP_13_18

    Article  Google Scholar 

  11. Chu-Shore CJ, Major P, Montenegro M, Thiele E (2009) Cyst-like tubers are associated with TSC2 and epilepsy in tuberous sclerosis complex. Neurology 72:1165–1169. https://doi.org/10.1212/01.wnl.0000345365.92821.86

    Article  Google Scholar 

  12. Jansen FE, Vincken KL, Algra A et al (2008) Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology 70:916–923. https://doi.org/10.1212/01.wnl.0000280579.04974.c0

    Article  CAS  Google Scholar 

  13. Pollock JM, Whitlow CT, Tan H et al (2009) Pulsed arterial spin-labeled MR imaging evaluation of tuberous sclerosis. AJNR Am J Neuroradiol 30:815–820. https://doi.org/10.3174/ajnr.A1428

  14. Widjaja E, Wilkinson ID, Griffiths PD (2007) Magnetic resonance perfusion imaging in malformations of cortical development. Acta Radiol 48:907–917. https://doi.org/10.1080/02841850701477686

    Article  CAS  Google Scholar 

  15. Fedi M, Reutens DC, Andermann F et al (2003) α-[11C]-Methyl-L-tryptophan PET identifies the epileptogenic tuber and correlates with interictal spike frequency. Epilepsy Res 52:203–213. https://doi.org/10.1016/S0920-1211(02)00216-4

    Article  Google Scholar 

  16. Chugani HT, Luat AF, Kumar A et al (2013) α-[11C]-Methyl-L-tryptophan--PET in 191 patients with tuberous sclerosis complex. Neurology 81:674–680. https://doi.org/10.1212/WNL.0b013e3182a08f3f

    Article  CAS  Google Scholar 

  17. Koh S, Jayakar P, Resnick T et al (1999) The localizing value of ictal SPECT in children with tuberous sclerosis complex and refractory partial epilepsy. Epileptic Disord 1:41–46

    CAS  Google Scholar 

  18. Benova B, Petrak B, Kyncl M et al (2018) Early predictors of clinical and mental outcome in tuberous sclerosis complex: a prospective study. Eur J Paediatr Neurol 22:632–641. https://doi.org/10.1016/j.ejpn.2018.03.001

    Article  Google Scholar 

  19. De Ridder J, Lavanga M, Verhelle B et al (2020) Prediction of neurodevelopment in infants with tuberous sclerosis complex using early EEG characteristics. Front Neurol 11:1151. https://doi.org/10.3389/fneur.2020.582891

    Article  Google Scholar 

  20. Baldini S, Coito A, Korff CM et al (2020) Localizing non-epileptiform abnormal brain function in children using high density EEG: Electric Source Imaging of focal slowing. Epilepsy Res 159:106245. https://doi.org/10.1016/j.eplepsyres.2019.106245

    Article  CAS  Google Scholar 

  21. Haller S, Zaharchuk G, Thomas DL et al (2016) Arterial spin labeling perfusion of the brain: emerging clinical applications. Radiology 281:337–356. https://doi.org/10.1148/radiol.2016150789

    Article  Google Scholar 

  22. Hully M, Grevent D, Breuillard D et al (2016) Arterial spin labeling shows pre-epileptic tuber hyperperfusion in tuberous sclerosis complex. Neurology 86:1744–1745. https://doi.org/10.1212/WNL.0000000000002636

    Article  Google Scholar 

  23. Northrup H, Krueger DA (2013) Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 49:243–254. https://doi.org/10.1016/j.pediatrneurol.2013.08.001

    Article  Google Scholar 

  24. Brunet O, Lézine I, Josse D (2001) Brunet-Lézine révisé : Echelle de développement psychomoteur de la première enfance: manuel BLR-C

  25. Park SE, Demakis GJ (2017) Wechsler preschool and primary scale of intelligence. In: Zeigler-Hill V, Shackelford TK (eds) Encyclopedia of personality and individual differences. Springer International Publishing, Cham, pp 1–4

    Google Scholar 

  26. Sparrow SS, Cicchetti DV, Saulnier CA (2016) Vineland adaptive behavior scales, Third Edition (Vineland-3). NCS Pearson, Bloomington

    Google Scholar 

  27. Rutter M, LeCouteur A, Lord C (2003) The autism diagnostic interview-revised, vol 24. West Psychol Serv, Los Angeles, pp 659–685

    Google Scholar 

  28. Lord C, Rutter M, DiLavore P, Risi S (2008) Autism diagnostic observation schedule (ADOS): manual. Western Psychological Services, Los Angeles

    Google Scholar 

  29. Makeig S, Bell AJ, Jung T-P, Sejnowski TJ (1998) Independent component analysis of electroencephalographic data. Adv Neural Inf Process Syst 8:145–151

    Google Scholar 

  30. Tao J, Chen X-J, Baldwin M et al (2011) Interictal regional delta slowing is an EEG marker of epileptic network in temporal lobe epilepsy. Epilepsia 52:467–476. https://doi.org/10.1111/j.1528-1167.2010.02918.x

    Article  Google Scholar 

  31. Tzourio-Mazoyer N, Landeau B, Papathanassiou D et al (2002) Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 15:273–289. https://doi.org/10.1006/nimg.2001.0978

    Article  CAS  Google Scholar 

  32. Peters JM, Prohl AK, Tomas-Fernandez XK et al (2015) Tubers are neither static nor discrete: evidence from serial diffusion tensor imaging. Neurology 85:1536–1545. https://doi.org/10.1212/WNL.0000000000002055

    Article  Google Scholar 

  33. Nishida M, Asano E, Juhász C et al (2008) Cortical glucose metabolism correlates negatively with delta-slowing and spike-frequency in epilepsy associated with tuberous sclerosis. Hum Brain Mapp 29:1255–1264. https://doi.org/10.1002/hbm.20461

    Article  Google Scholar 

  34. Kielar A, Deschamps T, Chu RKO et al (2016) Identifying dysfunctional cortex: dissociable effects of stroke and aging on resting state dynamics in MEG and fMRI. Front Aging Neurosci 8:40. https://doi.org/10.3389/fnagi.2016.00040

    Article  Google Scholar 

  35. Kulandaivel K, Holmes GL (2011) Power spectral analysis in infants with seizures: relationship to development. Epilepsy Behav 20:700–705. https://doi.org/10.1016/j.yebeh.2011.02.021

    Article  Google Scholar 

  36. Pendse N, Wissmeyer M, Altrichter S et al (2010) Interictal arterial spin-labeling MRI perfusion in intractable epilepsy. J Neuroradiol 37:60–63. https://doi.org/10.1016/j.neurad.2009.05.006

    Article  CAS  Google Scholar 

  37. Lemaître H, Augé P, Saitovitch A et al (2021) Rest functional brain maturation during the first year of life. Cereb Cortex 31:1776–1785. https://doi.org/10.1093/cercor/bhaa325

    Article  Google Scholar 

  38. Kotulska K, Kwiatkowski DJ, Curatolo P et al (2021) Prevention of epilepsy in infants with tuberous sclerosis complex in the EPISTOP Trial. Ann Neurol 89:304–314. https://doi.org/10.1002/ana.25956

    Article  CAS  Google Scholar 

  39. Samueli S, Dressler A, Gröppel G et al (2018) Everolimus in infants with tuberous sclerosis complex-related West syndrome: first results from a single-center prospective observational study. Epilepsia 59:e142–e146. https://doi.org/10.1111/epi.14529

    Article  CAS  Google Scholar 

  40. Fohlen M, Taussig D, Ferrand-Sorbets S et al (2018) Refractory epilepsy in preschool children with tuberous sclerosis complex: early surgical treatment and outcome. Seizure 60:71–79. https://doi.org/10.1016/j.seizure.2018.06.005

    Article  Google Scholar 

  41. Joo EY, Hong S, Tae W-S et al (2006) Effect of lamotrigine on cerebral blood flow in patients with idiopathic generalised epilepsy. Eur J Nucl Med Mol Imaging 33:724–729. https://doi.org/10.1007/s00259-005-0029-7

    Article  CAS  Google Scholar 

  42. Mori T, Ito H, Harada M et al (2020) Multi-delay arterial spin labeling brain magnetic resonance imaging study for pediatric autism. Brain Dev 42:315–321. https://doi.org/10.1016/j.braindev.2020.01.007

    Article  Google Scholar 

  43. Im K, Ahtam B, Haehn D et al (2016) Altered structural brain networks in tuberous sclerosis complex. Cereb Cortex 26:2046–2058. https://doi.org/10.1093/cercor/bhv026

  44. Tsai J-D, Ho M-C, Lee H-Y et al (2021) Disrupted white matter connectivity and organization of brain structural connectomes in tuberous sclerosis complex patients with neuropsychiatric disorders using diffusion tensor imaging. MAGMA 34:189–200. https://doi.org/10.1007/s10334-020-00870-4

Download references

Funding

This study was supported by a research grant from the French Society of Radiology (SFR).

Author information

Author notes

  1. Rima Nabbout and Nathalie Boddaert contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Radiology, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris cité, 149 rue de Sèvres, 75015, Paris, France

    Caroline Rutten, Volodia Dangouloff-Ros & Nathalie Boddaert

  2. Imagine Institute for Genetic Diseases, INSERM U1163, Paris, France

    Caroline Rutten, Ludovic Fillon, Mathieu Kuchenbuch, Ana Saitovitch, Jennifer Boisgontier, Nicole Chemaly, Volodia Dangouloff-Ros, Thomas Blauwblomme, Monica Zilbovicius, Rima Nabbout & Nathalie Boddaert

  3. Reference Centre for Rare Epilepsies, Department of Pediatric Neurology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris cité, 149 rue de Sèvres, 75015, Paris, France

    Mathieu Kuchenbuch, Nicole Chemaly, Delphine Breuillard & Rima Nabbout

  4. Department of Child Psychiatry, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris cité, 149 rue de Sèvres, 75015, Paris, France

    Lisa Ouss

  5. Department of Pediatric Neurosurgery, Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, University of Paris cité, 149 rue de Sèvres, 75015, Paris, France

    Thomas Blauwblomme

Authors
  1. Caroline Rutten
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ludovic Fillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mathieu Kuchenbuch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ana Saitovitch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer Boisgontier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicole Chemaly
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Delphine Breuillard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lisa Ouss
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Volodia Dangouloff-Ros
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Blauwblomme
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Monica Zilbovicius
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Rima Nabbout
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nathalie Boddaert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nathalie Boddaert.

Ethics declarations

Guarantor

The scientific guarantor of this publication is Pr Nathalie Boddaert.

Conflict of interest

The authors declare no competing interests.

Statistics and biometry

No complex statistical methods were necessary for this paper.

Informed consent

Written informed consent was not required for this study because this was a retrospective study using anonymized data.

Ethics approval

Institutional Review Board approval was not required because this was a retrospective study using anonymized data.

Methodology

  • retrospective

  • observational

  • performed at one institution

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(DOCX 1923 kb)

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rutten, C., Fillon, L., Kuchenbuch, M. et al. The longitudinal evolution of cerebral blood flow in children with tuberous sclerosis assessed by arterial spin labeling magnetic resonance imaging may be related to cognitive performance. Eur Radiol 33, 196–206 (2023). https://doi.org/10.1007/s00330-022-09036-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00330-022-09036-3

Keywords

Search

Navigation