Neurodevelopmental outcomes and neurophysiological parameters in children with congenital hyperinsulinism

Introduction. Congenital hyperinsulinism is a rare group of genetic disorders resulting in persistent hypoglycemia which can lead to delay of neurodevelopment.

Aim. To assess psychomotor development and certain neurophysiological parameters of children treated for congenital hyperin-sulinism.

Materials and methods. This prospective and retrospective cohort study included 73 infants with congenital hyperinsulinism admitted to the National Almazov Research Centre from 2017 to 2021. All subjects underwent standard clinical examination including physical and neurological assessment as well as 18F-DOPA PET/CT, genetic testing, electroencephalography. Developmental screening was performed using “Ages and Stages” questionnaire in 33 subjects. Possible risk factors for neurode-velopmental sequelae due to hypoglycemia were analyzed.

Results and discussion. Normal neurodevelopment in general was observed in 23 subjects (69%), 10 patients had developmental delay. Focal form of CHI had the greatest modifying effect on positive neurodevelopmental outcome in general. Individual skills such as communication, fine and gross motor, problem solving in children with a focal form of CHI were significantly better than those with a nonfocal forms. Age of manifestation and verification of the disease, the minimum level of glycemia and the maximum level of glucose utilization did not significantly affect the formation of either individual skills (with the exception of gross motor skills) or psychomotor development in general. The indicators of gross motor skills in children with a lower level of glucose utilization turned out to be significantly better. Kaplan-Meier survival analysis showed that the alpha rhythm appearance was significantly earlier in patients with a focal form of CHI and with earlier verification of the diagnosis (<28 days of life).

Conclusion. The focal form of the disease has the greatest modifying effect on the positive outcome of the psychomotor development. The age-appropriate gross motor skills were observed more often in the group of children with low glucose disposal rates. The association of the early occurrence of the alpha rhythm with the focal form of congenital hyperinsulinism, as well as with the early verification of the disease, was found.

1. Guemes M., Rahman S.A., Kapoor R.R., Flanagan S., Houghton J.A.L., Misra S. et al. Hyperinsulinemic hypoglycemia in children and adolescents: Recent advances in understanding of pathophysiology and management. Rev Endocr Metab Disord. 2020;21(4):577-597. https://doi.org/10.1007/s11154-020-09548-7.

2. Rasmussen A.G., Melikian M., Globa E., Detlefsen S., Rasmussen L., Petersen H. et al. The difficult management of persistent, non-focal congenital hyperinsu-linism: A retrospective review from a single, tertiary center. Pediatr Diabetes. 2020;21(3):441-455. https://doi.org/10.1111/pedi.12989.

3. Rother K.I., Matsumoto J.M., Rasmussen N.H., Schwenk W.F. Subtotal pancreatectomy for hypoglycemia due to congenital hyperinsulinism: long-term follow-up of neurodevelopmental and pancreatic function. Pediatr Diabetes. 2001;2(3):115-122. https://doi.org/10.1034/j.1399-5448.2001.002003115.x.

4. Dacou-Voutetakis C., Psychou F., Maniati-Christidis M. Persistent hyperinsulin-emic hypoglycemia of infancy: long-term results. J Pediatr Endocrinol Metab. 1998;11 Suppl 1:131-141. https://doi.org/10.1515/JPEM.1998.11.S1.131.

5. Mazor-Aronovitch K., Gillis D., Lobel D., Hirsch H.J., Pinhas-Hamiel O., Modan-Moses D. et al. Long-term neurodevelopmental outcome in conservatively treated congenital hyperinsulinism. Eur J Endocrinol. 2007;157(3):491-497. https://doi.org/10.1530/EJE-07-0445.

6. Sun H.-S., Feng Z.-P., Miki T., Seino S., French R.J. Enhanced neuronal damage after ischemic insults in mice lacking Kir6.2-containing ATP-sensitive K+ channels. J Neurophysiol. 2006;95(4):2590-2601. https://doi.org/10.1152/jn.00970.2005.

7. Warren R.E., Frier B.M. Hypoglycaemia and cognitive function. Diabetes Obes Metab. 2005;7(5):493-503. https://doi.org/10.1111/j.1463-1326.2004.00421.x.

8. Ludwig A., Ziegenhorn K., Empting S., Meissner T., Marquard J., Holl R. et al. Glucose metabolism and neurological outcome in congenital hyperinsu-linism. Semin Pediatr Surg. 2011;20(1):45-49. https://doi.org/10.1053/j.sempedsurg.2010.10.005.

9. Lord K., Radcliffe J., Gallagher P.R., Adzick N.S., Stanley C.A., De Leon D.D. High Risk of Diabetes and Neurobehavioral Deficits in Individuals With Surgically Treated Hyperinsulinism. J Clin Endocrinol Metab. 2015;100(11):4133-4139. https://doi.org/10.1210/jc.2015-2539.

10. Shield J.P. Fluorine-18 L-3,4-dihydroxyphenylalanine positron emission tomography: improving surgery and outcome in focal hyperinsulinism. Commentary to Mohnike et al.: Proposal for a standardized protocol for F-DOPA-PET (PET/CT) in congenital hyperinsulinism. Horm Res. 2006;66(1):43-44. https://doi.org/10.1159/000093472.

11. Giri D., Hawton K., Senniappan S. Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management. J Pediatr Endocrinol Metab. 2021;35(3):279-296. https://doi.org/10.1515/jpem-2021-0369.

12. Helleskov A., Melikyan M., Globa E., Shcherderkina I., Poertner F., Larsen A.M. et al. Both Low Blood Glucose and Insufficient Treatment Confer Risk of Neurodevelopmental Impairment in Congenital Hyperinsulinism: A Multinational Cohort Study. Front Endocrinol (Lausanne). 2017;8:156. https://doi.org/10.3389/fendo.2017.00156.

13. Roeper M., Salimi Dafsari R., Hoermann H., Mayatepek E., Kummer S., Meissner T. Risk Factors for Adverse Neurodevelopment in Transient or Persistent Congenital Hyperinsulinism. Front Endocrinol (Lausanne). 2020;11:580642. https://doi.org/10.3389/fendo.2020.580642.

14. Peterkova V.A., Bezlepkina O.B., Melikyan M.A., Gubaeva D.N., Bolmasova A.V., Petryaykina E.E. et al. Diagnosis and treatment of congenital hyperinsulinism in children: clinical guidelines. Moscow; 2021. 57 p. (In Russ.) Available at: https://rae-org.ru/system/files/documents/pdf/klinreki_vgi_final_1.pdf.

15. Najimidinova G., Faromuzova K. Care for Development in Three Central Asian Countries Report of a Process Evaluation in Tajikistan, Kyrgyz Republic, and Kazakhstan. UNICEF; 2011. 36 p. Available at: https://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.434.850&rep=rep1&type=pdf.

16. Beniczky S., Hirsch LJ., Kaplan P.W., Pressler R., Bauer G., Aurlien H., Br0gger J.C., Trinka E. Unified EEG terminology and criteria for nonconvulsive status epilepticus. Epilepsia. 2013;54(Suppl_6):28-29. https://doi.org/10.1111/epi.12270.

17. Navarro D.J., Foxcroft D.R. Learning statistics with jamovi: a tutorial for psychology students and other beginners. Version 0.75. 2022. 519 p. https://doi.org/10.24384/hgc3-7p15.

18. Meissner T., Wendel U., Burgard P., Schaetzle S., Mayatepek E. Long-term follow-up of 114 patients with congenital hyperinsulinism. Eur J Endocrinol. 2003;149(1):43-51. https://doi.org/10.1530/eje.0.1490043.

19. Menni F., de Lonlay P, Sevin C., Touati G., Peigne C., Barbier V. et al. Neurologic Outcomes of 90 Neonates and Infants with Persistent Hyperinsulinemic Hypoglycemia. Pediatrics. 2001;107(3):476-479. https://doi.org/10.1542/peds.107.3.476.

20. Mannisto J.M.E., Jaaskelainen J., Otonkoski T., Huopio H. Long-Term Outcome and Treatment in Persistent and Transient Congenital Hyperinsulinism: A Finnish Population-Based Study. J Clin Endocrinol Metab. 2021;106(4):e1542-e1551. https://doi.org/10.1210/clinem/dgab024.