Cognitive dysfunction

Many studies of T1DM report that hypoglycaemia can have a negative effect on cognitive functioning (41, 52-56). The human brain relies on a source of glucose in order to function optimally (52). Lack of glucose to the brain can lead to cognitive dysfunction, coma and seizures, as a result of hypoglycaemia. Reports suggest that the young are more susceptible to the symptoms of hypoglycaemia due the fact that glucose deprivation in the brain (neuroglycopenia) may occur at higher glucose levels than in adults (57). Although there are no official reports highlighting what these levels are, studies do report a difference between age groups. Jones et al. (58) compared the glycaemic thresholds of hypoglycaemia symptom onset between adolescent T1DM patients and non-diabetic adults. Results showed that these glycaemic thresholds were much higher for younger participants (4.9mmol.l vs 3.1mmol/l) suggesting that there is a difference in the way that glucose deprivation is experienced by these two distinct groups. Research, however, has primarily been conducted with adolescent vs adults and does not explore the difference between younger and older children (48). The impact of hypoglycaemia on cognitive functioning in children with early onset T1DM can be especially concerning. This group inevitably experiences more severe hypoglycaemic events due to their reduced ability at recognising or communicating the symptoms of hypoglycaemia in order for swift treatment. The fact that those with early onset T1DM have also been diagnosed at an early age means that they are likely to have experienced a greater number of episodes of hypoglycaemia than those diagnosed later in life.

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Conversely, the negative effects of hyperglycaemia on cognitive functioning have also been reported (53, 59, 60). Perantie et al. (53) studied the effects of both hypoglycaemia and hyperglycaemia on cognition. Their findings indicate that extreme BG levels (high or low) contribute to differing effects on cognitive functioning. Hyperglycaemia was found to affect verbal intelligence of CYP with T1DM whereas hypoglycaemia had an impact on spatial analysis and was linked with a delay in recall of learned information. This study will be discussed in more detail below. For the purposes of this study the focus will remain on the effects of hypoglycaemia on cognitive functions of CYP.

As previously mentioned, Perantie et al. (53) compared 117 T1DM children (aged 5-16 years) to their non-diabetic siblings (N=58) on cognitive performance. Children who had been diagnosed with diabetes before the age of five performed significantly worse on spatial relations than any other group. These children were also found to suffer more frequent episodes of hypoglycaemia, which highlighted how tight control can adversely affect a child’s cognitive development. The outcomes of this study should be treated cautiously, however, as the retrospective nature of the design does not allow any conclusions to be drawn regarding cause and effect. The sample used in this study was broken down into smaller sub groups which could have also had an impact on the analyses.

Conflicting evidence is reported by Strudwick et al. (61), who investigated the association of severe hypoglycaemia in young children with early onset T1DM with cognitive abnormalities. For this study, severe hypoglycaemia was defined as prior hypoglycaemia seizure/coma. The study compared three groups of diabetic children and adolescents who were diagnosed aged <6 years; one group had a history of severe hypoglycaemia at age<6 years; another group experienced their first severe hypoglycaemic episode after the age of 6 years; the last group was the T1DM control with no history of severe hypoglycaemia. Interestingly, no significant differences were detected between any of the groups on intellectual, memory or behavioural measures. Severe hypoglycaemia, in this study, was characterised only by episodes of seizures or coma and didn’t take into account severe hypoglycaemia without these events. Including a wider range of episodes of severe

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hypoglycaemia might have made a difference to the strength of relationships however, researchers would then have had to rely on retrospective and subjective data. Additionally, the small sample size may have impacted on this study’s ability to detect any significant results, although the researchers of this study stress that similar studies have also used comparable sized samples.

Ho et al. (62) used a similarly matched sample of diabetic children (those with a history of SH vs those without a history of SH) diagnosed with diabetes <6 years. Again, severe hypoglycaemia here was defined as a seizure/coma resulting from severe hypoglycaemia. Magnetic resonance imaging (MRI) was used to compare structural differences in the brain, between groups. Although significant differences were not found between the groups, the results of this study indicated that early onset T1DM was associated with central nervous system (CNS) abnormalities. Specifically, mesial temporal sclerosis (MTS) was evident in the entire cohort. MTS is unusual in those without seizure disorders so its presence in itself was an interesting finding. The implications of MTS on the brain are damage to the hippocampus, leading to long term memory deficits and problems with cognitive functions. MRI in children can be problematic due to the fact that these tests require participants to lie very still, in a confined space, albeit for a short period of time. This may have impacted on the quality and usability of the MRI scans (63). However, the study did objectively examine the structural effects of severe hypoglycaemia on the brain of this sample of children.

In spite of research which has focused on the link between severe hypoglycaemia and cognitive dysfunction, the topic remains controversial. McNay and Cotero (52) carried out a mini-review of research specific to the impact of recurrent hypoglycaemia. Their review looked at both human and animal studies and concluded that recurrent hypoglycaemia seemed to induce a positive brain response whereby an increased supply of fuel was directed to the brain, so that cognitive functions were supported rather than impaired. The authors however, also acknowledged that whilst the brain seemed to protect against hypoglycaemia, previous experiences of hypoglycaemia can interfere with the body’s ability to deal with further episodes of hypoglycaemia. Paired with the fact that recurrent

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hypoglycaemia also impacts on awareness of hypoglycaemia, there are still major implications of hypoglycaemia on those who are affected.