David A. Hepburn

Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin-treated diabetes mellitus

SummaryTo examine the hypothesis that episodes of severe hypoglycaemia may cause cumulative cognitive impairment, 100 Type 1 (insulin-dependent) diabetic patients were examined. Their age range was 25–52 years, and the onset of diabetes had occurred after the age of 19 years. Patients with evidence of organic brain disease, including cerebrovascular disease, were excluded. A questionnaire was used to assess the number, frequency and severity of hypoglycaemic episodes experienced during treatment with insulin and the accuracy of this retrospective information was verified from general practice and hospital case-notes. A detailed neuropsychological assessment was undertaken, including tests of pre-morbid and present IQ (Wechsler-Revised), memory and information-processing speed. Significant correlations were observed between the frequency of severe hypoglycaemia and the magnitude of intellectual decline, Performance IQ, inspection time and reaction time (patients with the more frequent hypoglycaemia had poorer performance). Two sub-groups of patients were identified on the basis of their experience of severe hypoglycaemia, and were balanced for pre-morbid IQ, age and duration of diabetes. One sub-group (n=23) had never experienced severe hypoglycaemia (Group A), whilst the other sub-group (n=24) had suffered at least five episodes of severe hypoglycaemia (Group B). Group B had greater intellectual impairment than Group A, and Group B also had a significantly slower mean reaction time and higher reaction time variance when compared with Group A. It is concluded that recurrent severe hypoglycaemia is associated with cumulative cognitive impairment in adult diabetic patients treated with insulin.

Partitioning the symptoms of hypoglycaemia using multi-sample confirmatory factor analysis.

SummaryThe allocation of hypoglycaemic symptoms to autonomie or neuroglycopenic groups tends to occur on an a priori basis. In view of the practical need for clear symptom markers of hypoglycaemia more scientific approaches must be pursued. Substantial evidence is presented from two large scale studies we performed which support a three factor model of hypoglycaemic symptomatology, based on the statistical associations discovered among symptoms reported by diabetic patients. Study 1 involved 295 insulin-treated outpatients and found that 11 key hypoglycaemic symptoms segregated into three clear factors: autonomie (sweating, palpitation, shaking and hunger) neuroglycopenic (confusion, drowsiness, odd behaviour, speech difficulty and incoordination), and malaise (nausea and headache). The three factors were validated on a separate group of 303 insulin-treated diabetic out-patients. Confirmatory factor analyses showed that the three factor model was the optimal model for explaining symptom covariance in each group. A multi-sample confirmatory factor analysis tested the rigorous assumptions that the relative loadings of symptoms on factors across groups were equal, and that the residual variance for each symptom was identical across groups. These assumptions were successful, indicating that the three factor model was replicated in detail across these two large samples. It is suggested that the results indicate valid groupings of symptoms that may be used in future research and in clinical practice.

Severe Hypoglycemia and Intelligence in Adult Patients With Insulin-Treated Diabetes

The IQ scores (WAIS-R) of 100 patients with insulin-treated diabetes (aged 25–52 yr) were compared with those of 100 healthy control subjects who were matched to the diabetic patients for sex, age, education, and social class. The diabetic group had lower WAIS-R performance and verbal IQ scores than the control group (P = 0.017 and P = 0.033, respectively) after controlling for premorbid IQ. The extent of the difference was modest, representing ∼33% of an SD in IQ. When frequency of severe hypoglycemia was controlled for the difference in performance IQ between the diabetic patient group and the control group was abolished, whereas the difference between the groups in verbal IQ persisted. It is hypothesised that cumulative severe hypoglycemia might be the major factor in the slight performance IQ differences between diabetic patients and control subjects. The origin of the verbal IQ differences, although obscure, might be related to the social impact of the disorder.

Regional cerebral blood flow in IDDM patients: effects of diabetes and of recurrent severe hypoglycaemia.

SummaryChronic hyperglycaemia and recurrent severe hypoglycaemia have both been implicated as causing cerebral damage in patients with diabetes. Although cognitive dysfunction and intellectual impairment have been demonstrated in patients with recurrent severe hypoglycaemia, structural correlates have not been described, and it is not known whether specific functional changes occur in the brains of affected patients. Regional cerebral blood flow was estimated by SPECT with 99mTechnetium Exametazime in 20 patients with IDDM. Ten patients had never experienced severe hypoglycaemia and 10 had a history of recurrent severe hypoglycaemia. Patient results were compared with 20 age- and sex-matched healthy volunteers. We observed differences between the two patient groups and the control group. Tracer uptake was greater in diabetic patients in the superior pre-frontal cortex. This effect was particularly pronounced in the group who had a history of previous severe hypoglycaemia. Patients with a history of recurrent hypoglycaemia also had a relative reduction in tracer uptake to the calcarine cortex. This suggests an alteration in the pattern of baseline regional cerebral blood flow in diabetic patients with frontal excess and relative posterior reduction in cerebral blood flow.

WHICH ABILITIES DOES THE PASAT TEST

Abstract The relationships between PASAT test scores and intelligence, memory and information processing abilities were examined in ninety-four healthy young adult patients with type 1 (insulin-dependent) diabetes. PASAT scores correlated significantly with all WAIS-R subtests. Factor analysis revealed that PASAT performance loaded on the 1st principal component (the ‘general intelligence’ factor) at about the same level as some WAIS-R performance subtests. Varimax rotation showed that PASAT scores had very low loadings on verbal and performance factors, but had high loadings on the third rotated factor, which was tentatively identified as the ‘freedom from distraction’ factor found in recent factor analyses of the WAIS-R. Scores from the 4 second PASAT presentation correlated better than 2 second PASAT scores with indices derived from the Rey auditory verbal learning test, whereas the faster PASAT test correlated at higher levels with test of Inspection Time and Reaction Time. The PASAT test was developed to measure attention and concentration but, while this appears to have been realised to some extent, general intellectual ability is also tapped by the test. Different speeds of presentation might index other abilities to different degrees, but this finding might be explained by order effects which cannot be excluded by the present study.

Structural equation modeling of symptoms, awareness and fear of hypoglycemia, and personality in patients with insulin-treated diabetes

OBJECTIVE To assess the possible influence of personality on self-reported awareness, symptoms, and fear of hypoglycemia and also to identify the relationship among these self-reported measures using formal structural equation modeling. RESEARCH DESIGN AND METHODS A structured questionnaire, which included questions about sociodemographic details, awareness of the onset of hypoglycemia, and a list of symptoms of hypoglycemia, was completed by 305 consecutive insulin-treated diabetic patients attending the diabetic clinic at the Royal Infirmary of Edinburgh. They also completed the Hypoglycemia Fear Survey (HFS), and personality was assessed using the short form of the shortened Eysenck Personality Questionnaire-Revised (EPQ-R). Formal structural equation modeling was performed using the following variables: awareness, autonomic symptoms, neuroglycopenic symptoms, severe hypoglycemic episodes in the last year, worry and behavior (from the HFS), and extroversion and neuroticism (from the short EPQ-R). This allowed a model to be constructed that expressed the putative causal associations among the variables that could be tested statistically. RESULTS Of the 302 patients who had experienced hypoglycemia, 111 (37%) reported reduced awareness, and these patients scored higher on the worry subscale of the HFS (reduced awareness: 41 ± 12 vs. normal awareness: 34 ± 12, P < 0.001). The patients with reduced awareness scored higher for neuroticism than did the patients with normal awareness (reduced awareness: 6.1 ± 3.4 vs. normal awareness: 4.9 ± 3.3, P < 0.01) and scored lower for extroversion (reduced awareness: 5.8 ± 3.7 vs. normal awareness: 7.1 ± 3.7, P < 0.01). In the structural equation modeling exercise, neuroticism was a significant putative determinant of many of the other variables. CONCLUSIONS Personality was the major determinant of the variance that could be accounted for in this study and influenced self-reported symptoms, awareness, and fear of hypoglycemia. Personality factors may, therefore, influence self-reports from patients, particularly when soft measures, such as symptoms, are assessed and even when using validated clinical questionnaires. This finding stresses the importance of using additional evidence, such as reports from relatives, to substantiate reports from patients of loss of hypoglycemia awareness.

The effects of acute hypoglycemia on relative cerebral blood flow distribution in patients with type I (insulin-dependent) diabetes and impaired hypoglycemia awareness

To examine the hypothesis that in diabetic patients with impaired hypoglycemia awareness the relative regional distribution of cerebral blood flow (rCBF) would be abnormal in a specific area, namely the frontal lobes, rCBF was examined in 20 type I diabetic patients, of whom 10 had a normal awareness of hypoglycemia and 10 had a history of impaired hypoglycemia awareness. rCBF was determined sequentially using single photon emission computed tomography (SPECT) during (1) normoglycemia (arterialized blood glucose 4.5 mmol. L-1) and (2) hypoglycemia (blood glucose 2.5 mmol.L-1) induced by a hyperinsulinemic glucose clamp technique. Distribution of the isotope, 99mTc-Exametazime, was detected using a single-slice multi-detector head scanner. A split-dose technique was used, with 250 MBq being injected during steady-state normoglycemia and 250 MBq during subsequent hypoglycemia. rCBF was estimated in 30 regions of interest, derived from a standard neuroanatomical atlas on two parallel slices at 40 and 60 mm above the orbitomeatal line (OML). No between-group differences in the pattern of overall rCBF or changes in regional tracer uptake were demonstrated. In comparison to the rCBF during normoglycemia, both patient groups exhibited significant changes in the pattern of rCBF during hypoglycemia, with increments of rCBF to both superior frontal cortices and the right thalamus and reduced rCBF to the right posterior cingulate cortex and the right putamen. This pattern of relative redistribution of rCBF during hypoglycemia was preserved in patients who had impaired hypoglycemia awareness.

Hypoglycemic Convulsions Cause Serious Musculoskeletal Injuries in Patients With IDDM

Six diabetic patients are described who sustained serious musculoskeletal injuries during insulin-induced hypoglycemia. The convulsions were associated with nocturnal hypoglycemia, superoptimal glycemic control, pregnancy, hypoglycemic unawareness, or errors in selfmanagement.

PASAT performance and the pattern of uptake of 99mTc-exametazime in brain estimated with single photon emission tomography.

The effect of the paced auditory serial addition test (PASAT) on the regional uptake of 99mTc-exametazime was determined by single photon emission computed tomography. Twenty insulin-treated diabetic outpatients were scanned at rest and during the performance of the PASAT task using split-dose injection of tracer. When resting and activation scans were compared there were significant decreases in tracer uptake in the right anterior cingulate and left posterior cingulate areas during PASAT activation. The findings are compared with previous studies which had implicated the anterior cingulate area in the mechanisms of attention in humans and other animals. The potentially confounding role of anxiety during attentional tasks is discussed.

Physiological manipulation of psychometric mood factors using acute insulin-induced hypoglycaemia in humans

Abstract According to Thayer ( The Biopsychology of Mood and Arousal , 1989), the mood states of tense arousal and energetic arousal correlate negatively during ‘tense tiredness’. In the present study, acute insulin-induced hypoglycaemia was used to induce tense tiredness. It was hypothesized that levels of tense arousal would be associated with the autonomic manifestations of hypoglycaemia and that energetic arousal levels would be associated with the neuroglycopenic effects of acute hypoglycaemia. Measurements of mood state, symptom score, haemodynamic responses and plasma catecholamine concentrations were made during hypoglycaemia induced by an i.v. infusion of insulin, in 12 healthy male subjects and 15 patients with Type 1 (insulin-dependent) diabetes. Tense arousal rose in both groups of subjects to a peak which coincided with the onset of the acute autonomic reaction, identified by the rapid increase in heart rate and changes in blood pressure which result from neural stimulation within the hypothalamus caused by neuroglycopenia. Energetic arousal decreased significantly in both groups coincidental with the rise in tense arousal and the onset of the acute autonomic reaction. These changes in mood state were concurrent with increments in autonomic and neuroglycopenic symptom scores. This experimental model has allowed induction of a state of ‘tense-tiredness’ in normal and diabetic humans by using acute hypoglycaemia as a stressful stimulus, confirming to some degree the independence of the two orthogonal mood factors, tense arousal and energetic arousal.