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Neuroimaging, Cognitive and Metabolic Profiles in Children with Hypoglycaemia

Kumaran, A; (2013) Neuroimaging, Cognitive and Metabolic Profiles in Children with Hypoglycaemia. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Background: Glucose is a major fuel for brain function, and persistent and recurrent hypoglycaemia of any aetiology can cause brain injury. Children with hyperinsulinaemic hypoglycaemia (HH) are at a high risk of brain injury, as the inappropriate secretion of insulin during hypoglycaemia inhibits lipolysis thereby reducing the availability of ketone bodies (KB) that are an important source of alternate fuel for the brain during hypoglycaemia. In contrast children with ketotic hypoglycaemia (KH) are believed to be neurologically protected, due to the presence of abundant ketone bodies during hypoglycaemia. However, in both these groups of children, a comprehensive assessment of the neurocognitive profile with correlation to neuroimaging is not available. Aims: The aims of this thesis are 1. To understand the magnitude and rate of ketone body response during a diagnostic fast between children with KH and a ‘control’ group (children with suspected or previous history of hypoglycaemia that were subsequently normoglycaemic on the diagnostic fast). 2. To investigate and compare the neurocognitive profiles of children with HH and KH (used as a control group), and to correlate the profile of deficits in the HH group to the underlying structural abnormalities. The studies on children with KH (biochemical, neurocognitive and neuroimaging) were utilised to understand the neuroprotective role of KB during hypoglycaemia. Methods: 30 children with KH and 74 children from the ‘control’ group underwent a diagnostic fast with measurements of plasma glucose, lactate, catecholamines and serum insulin, cortisol, growth hormone, non-esterified fatty acids (NEFA) and 3-βhydroxybutyrate (ketone body) concentrations at the beginning, middle and end of fast. The neurocognitive profile of 21 children with HH was compared to a group of 14 children with KH, using a combination of standardised tests to investigate IQ, memory, attention, academic attainment, movement, emotion and behaviour. The structural integrity of the brain was evaluated using conventional neuroradiological assessments, hippocampal volumetry and diffusion tensor imaging (DTI). Results: Fasting studies have shown that children with KH demonstrate a significant increase (87% per hour) in the rate and magnitude of 3-βhydroxybutyrate concentrations relative to ‘controls’. Cortisol concentrations are a significant predictor of KB concentrations at the end of the fast. The performance of KH children as a group was within the normal range for the neurocognitive measures. However four children in the KH group scored in the borderline (77-79) and low average range (81-84) for full scale IQ, and memory scores in one KH child was lower than predicted by 19 points. Neuroimaging revealed small hippocampi in one child, focal white matter lesions in two children and diffuse white matter lesions in two children with KH. Children with HH underperformed significantly (relative to KH and standard population means) in the tests for intelligence (especially perceptual reasoning), memory, and sustained attention and manual dexterity. Memory impairments in children with HH did not correlate with hippocampal pathology. However, analysis of DTI studies has revealed the presence of white matter microstructural deficits that correlate with IQ and perceptual reasoning indices in these (HH) children. The genu and splenium of the corpus callosum were highlighted as specific white matter regions vulnerable to injury in the HH group. Conclusions: Children with hypoglycaemia are at risk of white matter injury. Children with HH manifest widespread cognitive deficits that are partly explained by the white matter microstructural deficits noted in the DTI studies. The increased rate and magnitude of KB response in KH group during fasting supports increased metabolic utilisation and a glucose sparing effect. However some chidren with KH in this study exhibit white matter injury and a wide variation in the neurocognitive scores is also noted, indicating the presence of neurocognitive impairment in certain children with KH.

Type: Thesis (Doctoral)
Title: Neuroimaging, Cognitive and Metabolic Profiles in Children with Hypoglycaemia
Open access status: An open access version is available from UCL Discovery
Language: English
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
URI: https://discovery.ucl.ac.uk/id/eprint/1405622
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