Hypoglycaemia and Mental Functions in Children and Adolescents

There is controversy about whether repeated episodes of severe hypoglycaemia have lasting effects on the thinking skills of children (Ryan et al., 2005). In addition to the severity of hypoglycaemia, the age of the individual is important in determining the potential impact of hypoglycaemia on the brain (Ack et al., 1961). The human brain develops rapidly until the age of five years, and during this critical period any insult can have long-lasting effects. In diabetic children important risk factors for the development of later cognitive impairment are as follows (Ryan, 1988; 1997):

• early onset of diabetes;

• long duration of diabetes;

• poor metabolic control;

• severe hypoglycaemia.

Children with type 1 diabetes who suffer repeated and severe hypoglycaemia while younger than five years old have lower mental abilities later on in life, and may show more difficult behaviour (Ryan et al., 1984; Rovet et al., 1987; Golden et al., 1989; Hershey et al., 2005; Ryan et al., 2005). The combination of an early onset of diabetes (before five years of age) and recurrent severe hypoglycaemia appears to be associated with reduced attention, psychomotor efficiency, and spatial memory in adolescence (Rovet and Alvarez, 1997; Bjorgaas et al., 1997; Hershey et al., 2005). Adolescents who had developed type 1 diabetes after the age of five years have been shown to have lower verbal IQ than their peers, but this may be related in part to learning-related problems at school and loss of formal education rather than with hypoglycaemia (Fallstrom, 1974; Ryan et al., 2005).

Most of the studies mentioned above are cross-sectional, that is, they have tested groups of children, with and without diabetes, and have tried to review the children's clinical records to estimate the amount of previous hypoglycaemia experienced by each child with diabetes. A more robust type of study is one in which groups of children are followed prospectively. One such study is ongoing in Melbourne, Australia (Northam et al., 1995). Over 100 children with newly diagnosed type 1 diabetes have been compared with a matched control group of non-diabetic children. No differences in mental abilities or in educational attainments were discernible between the two groups. Therefore, when children develop type 1 diabetes they do not begin with any mental decrements when they are compared with their non-diabetic peers. An initial report from this invaluable study indicated that within two years of the development of diabetes the mental abilities of the diabetic children may begin to lag behind their non-diabetic peers (Northam et al., 1998). Six years after diagnosis, diabetic children performed worse than non-diabetic controls across a range of cognitive performance tests, while severe hypoglycaemia was associated with poorer verbal and IQ scores (Northam et al., 2001). However, the roles of hyper- and hypoglycaemia and other possible effects of having diabetes in promoting these changes, such as increased school absence, remain to be elucidated.

Another study of 41 children with early onset (< 6 years) type 1 diabetes found no association between severe hypoglycaemia and cognition (Strudwick et al., 2005). Their episodes of severe hypoglycaemia were recorded prospectively and their scores on IQ, memory, behaviour problems and depression did not differ from those of 43 non-diabetic peers. Intensive insulin therapy is associated with more severe hypoglycaemia and might be associated with cognitive decrements. An 18-month-longitudinal study of 142 children aged 6 to 15, who were randomised to either intensive therapy or conventional care, found no association between the occurrence or frequency of severe hypoglycaemia and a wide range of cognitive functions (Wysocki et al., 2003).

Examination of electroencephalograms (EEGs), the electrical signals that can be detected from living brains (Haumont et al., 1979), and of visual evoked potentials (signals generated in the brain in response to a stimulus) (Seidl et al., 1996), has found that abnormalities are commoner in children with early-onset diabetes who have had recurrent severe hypoglycaemia. The brain's electrical responses to stimuli are significantly slowed in almost three-quarters of adolescents with type 1 diabetes (Uberall et al., 1996). However, this same study found no differences in the mental ability of children with diabetes when they were compared to non-diabetic controls, and the neurophysiological changes in the diabetic children were not related to age at onset of diabetes, duration of diabetes, quality of metabolic control or the presence of peripheral neuropathy. In children, repeated exposure to severe hypoglycaemia has its most deleterious effects on the front and central regions of the brain's cerebral hemispheres (Bjorgaas et al., 1996). During controlled, modest hypoglycaemia induced in the laboratory, the EEGs of children with diabetes were more disturbed than those of non-diabetic children (Bjorgaas et al., 1998).

There are few brain-imaging studies examining the effects of severe hypoglycaemia on children. One small study using single photon emission tomography imaging found some evidence of mild dominant hemisphere dysfunction in diabetic children with a history of severe hypoglycaemia compared to an age-matched diabetic group with no history of severe hypoglycaemia (Tupola et al., 2004).

In summary, there is convincing evidence to suggest that children with type 1 diabetes who have repeated exposure to severe hypoglycaemia, especially when this occurs below the age of five years, will subsequently have lower mental ability levels with evidence of detrimental effects on the physiological activity of their brains.

Evidence for Neuropsychological Deterioration Following Repeated Hypoglycaemia in Adults

Adults with type 1 diabetes perform less well on mental ability tests than non-diabetic subjects (Ryan, 1988; Ryan et al., 2005), but the differences are subtle and the underlying causes unclear. This is a complex and difficult area of clinical research with a number of possible causative factors that are hard to tease apart; these include the metabolic disturbances of diabetes and its treatment, and the social and educational impact of chronic illness on intelligence. A few carefully-controlled studies have focused on adult subjects with insulin-treated diabetes who have a history of severe recurrent hypoglycaemia. These patients seem to recover mentally and physically after each episode of hypoglycaemia, but when they are tested in the laboratory with standardised mental tests they display subtle chronic impairment of some mental functions. Abnormal neurological symptoms and signs are usually absent. The evidence from the small number of retrospective studies that are available indicates an association between a history of recurrent severe hypoglycaemia and a modest reduction in IQ (Deary, 1993). The main findings from some of the more influential studies can be summarised as follows:

Figure 13.1 Pre-morbid (tinted bars) and present (white bars) IQ levels for Group A (subjects with type 1 with no history of severe hypoglycaemia) and Group B (subjects with type 1 with at least five episodes of severe hypoglycaemia). Pre-morbid versus present IQ comparison for Group A is non-significant, comparison for Group B is significant at p< 0.001. Reproduced from Langan et al. (1991). With kind permission from Springer Science and Business Media

Figure 13.1 Pre-morbid (tinted bars) and present (white bars) IQ levels for Group A (subjects with type 1 with no history of severe hypoglycaemia) and Group B (subjects with type 1 with at least five episodes of severe hypoglycaemia). Pre-morbid versus present IQ comparison for Group A is non-significant, comparison for Group B is significant at p< 0.001. Reproduced from Langan et al. (1991). With kind permission from Springer Science and Business Media

1. Wredling et al. (1990) performed a carefully controlled study in two small groups of patients with type 1 diabetes, with and without histories of recurrent severe hypoglycaemia. They demonstrated impaired performance on a number of mental function tests in the group with a history of severe hypoglycaemia. The study design could not exclude the possibility that the patients with a history of hypoglycaemia had a lower pre-morbid IQ.

2. Langan et al. (1991) conducted a study in 100 patients with type 1 diabetes, using more detailed tests of cognitive functions. Within this sample of people with diabetes, the group of patients with more than five episodes of severe hypoglycaemia displayed a small, but significant, decline in IQ (averaging about six IQ points) compared to the diabetic patients who had experienced no episodes of severe hypoglycaemia (Figure 13.1). Pre-morbid IQ was similar in patients with and without severe hypoglycaemia, thus strengthening the hypothesis that repeated, severe hypoglycaemia was responsible for the lower IQ (Langan et al., 1991; Deary et al., 1993). Taking the 100 diabetic patients as a whole, they had lower IQs than healthy, non-diabetic subjects with similar ages and social and educational backgrounds (Deary et al., 1993). Impaired performance IQ was closely associated with repeated, severe hypoglycaemia. Making decisions and initiating responses appeared to be affected specifically by recurrent severe hypoglycaemia (Deary et al., 1992). Verbal IQ was lower in people with type 1 diabetes compared to healthy control subjects, regardless of their history of hypoglycaemia. This may result from the social impact of the disorder (Deary et al., 1993).

3. The results of Langan et al. (1991) have been confirmed by another team of researchers (Lincoln et al., 1996) using an identical study design.

4. A small group of patients with type 1 diabetes has been described (Gold et al., 1994), in which the individuals have suffered many episodes of severe hypoglycaemia over several years of treatment with insulin, and have subsequently developed severe mental and memory problems and devastating social and psychological deficits, causing premature retirement from employment and disrupting social and family life.

Retrospective studies suggest that recurrent severe hypoglycaemia has a detrimental effect on cognitive functions. By contrast, the limited evidence from prospective studies of intensified insulin therapy, namely the Diabetes Control and Complications Trial (DCCT) (The Diabetes Control and Complications Trial Research Group, 1996) and the Stockholm Diabetes Intervention Study (Reichard and Pihl, 1994), appears to indicate that cognitive function does not deteriorate in patients who suffer recurrent hypoglycaemia, at least in the timescale (less than ten years) of these studies.

It cannot be concluded for certain that recurrent severe hypoglycaemia causes significant long-term effects on cognitive function (Deary, 1997). Indeed, there is better evidence to suggest that chronic hyperglycaemia is a more likely cause of cognitive decrements in people with diabetes (Ferguson et al., 2003; Ryan et al., 2005; Ferguson et al., 2005), and a recent meta-analysis of the effects of type 1 diabetes on cognitive performance found that, overall, repeated severe hypoglycaemia was not associated with cognitive decrements (Brands et al., 2005). However, showing no effect of repeated severe hypoglycaemia on cognitive functions is not equivalent to there being no effect on the brain. In one study of diabetic patients with and without histories of severe hypoglycaemia, no cognitive test score difference was evident, but the severe hypoglycaemia group had EEG changes indicative of decreased vigilance (Howorka et al., 2000).

The benefits of strict glycaemic control in reducing the microvascular complications of diabetes are undoubted, but there is a price to pay: a substantial increase in the risk of severe hypoglycaemia. Within the timescale of the original study, the DCCT cohort did not suffer a detrimental effect in cognitive function. The results of the long-term follow-up (average 18 years) of 75% of the original cohort (in the Epidemiology of Diabetes Interventions and Complications Study -EDIC), have shown that exposure to episodes of hypoglycaemic coma or seizure had no significant effect on cognitive function (The DCCT/EDIC Research Group, 2007). This is very reassuring, but the DCCT participants were young, highly motivated, of above average intelligence, free of advanced complications with no history of severe hypoglycaemia before entering the study, and they received a very high level of support from health professionals. In most diabetes outpatient clinics where resources are limited, such model patients are not the norm. It seems entirely justifiable to aim for strict glycaemic control for patients who fit the entry criteria used in the DCCT. It is probably also appropriate to extrapolate the lessons of the DCCT to older patients with more advanced diabetic complications and reasonable life expectancy, who have not previously experienced recurrent severe hypoglycaemia. There still remains a sizeable group of patients with type 1 diabetes whose glycaemic control is sub-optimal by the standards of the DCCT, and yet they have suffered recurrent severe hypoglycaemia in the past. The targets of glycaemic control should be set less rigidly for these patients, who are entitled to be informed of the potential risks of further hypoglycaemia on cognitive function.

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