1) A History of recurrent Severe Hypoglycaemia in Adults with Insulin-Dependent Diabetes is associated with Brian Atrophy, by Perros et al, Edinburgh, November 1996.

'11 patients with a history of 5 or more severe episodes of hypoglycaemia were scanned by MRI. 9 patients had abnormal scans. Two types of abnormality were observed namely high intensity rounded lesions distributed in the periventricular white matter and cortical atrophy.'

2) Severe Hypoglycaemia and cognitive impairment in diabetes, by Deary, Frier, Edinburgh, BMJ, 28.9.1996

'The Average cerebral impact of several episodes of severe hypoglycaemia over a period of between 5 and 15 years is either mild or negligible. For a few individuals, with vulnerability factors which as yet remain obscure, brain function may be permanently and importantly affected.'

3) Severe deterioration in Cognitive Function and Personality in Five Patients with Long-standing Diabetes: A Complication of Diabetes or a Consequence of Treatment? By Gold et al, Pittsburgh USA, Diabetologia 1993, 36

4) Permanent Neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Wredling et al. Sweden and Norway. Diabetologia 1990, 33.

5) Cognitive dysfunction in adults with type 1 (insulin-dependent) diabetes mellitus of long duration: effects of recurrent hypoglycaemia and other chronic complications, by Ryan et al, Pittsburgh USA, Diabetologia 1993, 36.

'A Single episode of moderate hypoglycaemia can readily produce a transient disruption in cognitive functioning. Studies using the insulin-glucose clamp technique have repeatedly demonstrated that when plasma glucose levels are experimentally reduced below 2.8mmol/l both diabetic and non-diabetic subjects often show a marked decline in mental efficiency.'

'Although the excitotoxic hypothesis of neuronal necrosis is based upon animal studies in which a single episode of very severe hypoglycaemia is maintained for at least 30 minutes it is not inconceivable that repeated episodes of moderate hypoglycaemia would, over time, have cumulative effect that leads to significant neuronal damage in humans.'

'Subjects were asked if they ever had an episode of hypoglycaemia so severe that you sought medical help (emergency room doctor). Whenever possible, estimates were corroborated by another family member, and by review of medical records.'

'Moreover clinical case reports have indicated that a single episode of severe hypoglycaemia may produce a variety of transient of permanent neurological disorders including hemiplegia, amnesia and coma while neuropathological studies have demonstrated the presence of hypoglycaemic associated neuronal necrosis in the cortex, hippocampus, and basal ganglia of humans and animals.'

'Neurophysiologic and neuro imaging studies have demonstrated that diabetic adults with a history of poor metabolic control have clear evidence of brain dysfunction. This has been demonstrated most convincingly by Dejgaard et al who studied 20 middle aged diabetic adults, all of whom had evidence of peripheral neuropathy. Abnormal brain stem auditory evoked potentials were found in 40% of these subjects, and abnormal magnetic resonance imaging results (characterised as lesions 2-10mm in size) were found in 69% of the diabetic subjects.'

'There can be no doubt that a severe episode of hypoglycaemia may result in significant brain dysfunction.'

6) Intensified conventional insulin treatment and neuropsychological impairment, by Reichard et al, Sweden, BMJ 7.12.1991, 303.

'Episode hypoglycaemia might cause permanent brain damage.'

7) Severe Hypoglycaemia and intelligence in adult patients with insulin- treated diabetes, by Dreary et al, Edinburgh and Aberdeen, Diabetes February 1993, 42.

8) Cumulative cognitive impairment following recurrent severe hypoglycaemia in adult patients with insulin- treated diabetes mellitus, by Langan et al, Edinburgh, Diabetologia 1991, 34.

'A 'Mild' episode of hypoglycaemia was defined as one which was self treated during which there had been no alteration in conscious level, while a 'severe' episode required external assistance for recovery, whether or not loss of consciousness had occurred.'

9) Effect of Long-Term Glycaemia Control on Cognitive Dysfunction, by Lincoln et al, Nottingham, Diabetes Care, June 1996, 19.6.

10) Complications in IDDM are caused by elevated blood glucose level: The Stockholm Diabetes Intervention Study (SDIS) at 10-year Follow up, by Reichard et al, Stockholm, Upsala, Sweden, Diabetologia 1996, 39.

'All Patients were followed up with regard to mortality, ketoacidosis, body mass index and severe hypoglycaemia (requiring help from someone else). The effects of severe hypoglycaemia on cognitive function were followed with a battery of computerised tests.'

'During the last 2.5 years of the study eight patients from each group needed emergency hospital care and intravenous glucose. Five patients in the ICT group and two patients from the ST group received subcutaneous or intramuscular injections of glucogen outside of hospital during the same period.'

11) Recurrent Severe Hypoglycaemia and Cognitive Function in Type 1 Diabetes, by Gold et al, Edinburgh, Diabetes Medicine 1993, 10.

12) Neurobehavioural Complications of Type 1 Diabetes, Examination of Possible Risk Factors, by Ryan, Pittsburgh, USA, Diabetes Care, January 1988, 11.'

'A very different set of risk factors has been identified in diabetic adults. Perhaps the most potent of these is profound hypoglycaemia. After a hypoglycaemia episode, the diabetic patient may develop intellectual impairments that range from merely a slight decrease in learning efficiency or eye hand coordination to severe impairment in virtually all cognitive domains.'

13) Effects of Intensive Diabetes Therapy on Neuropsychological Function in Adults in the Diabetes Control and Complications Trial by the DCCT Research Group, Bethesda, USA, Annals of Internal Medicine, 5.2.1996, 124.

'Although animal studies have provided the most compelling evidence for hypoglycaemia induced brain dysfunction, investigators of several recent cross sectional studies have concluded that five or more episodes of severe hypoglycaemia may be associated with mild cognitive impairment, as measured by performance on neuropsychological test.'

'Severe hypoglycaemic episodes were defined as those in which the patient had incapacity sufficient to require the assistance of another person.'

'Approximately one third of severe hypoglycaemic episodes involved coma seizure, or suspected seizure.' 'In the intensive treatment group, 16 severe hypoglycaemic episodes involving coma, seizure or suspected seizure occurred per 100 patients - years compared with 5 such episodes in the conventional treatment group.'