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.’
14) Post hypoglycaemic Encephalopathy, case reports, by George M Jones, M.D. American Journal of Medical Services, 1947, 213.
‘The Clinical entity post hypoglycaemic encephalopathy, has been previously reported under headings of synonyms such as fatal hypoglycaemia, mental deterioration associated with convulsions and hypoglycaemia, cerebral damage from insulin shock, irreversible or hypoglycaemic insulin coma, fatal hyper insulinism with cerebral lesions due to pancreatic adenoma, and post hypoglycaemic coma or syndrome, and psychiatric complications of hypoglycaemia in children. Even before the introduction of insulin, Joslin recognised that hypoglycaemia was a very serious factor in the treatment of diabetes.’
In 1932′ Terplan reported the case of a 16 year old boy who did not regain consciousness for 3 days after insulin shock, the blood sugar levels being normal for these 3 days. Post-mortem examination showed extreme oedema of the brain and destruction of ganglion cells.’ Wilder wrote:’ a feature of this type of coma (hypoglycaemia) that is very characteristic is its rapid termination when glucose is administered.’
Case 1 – 26 year old white man, diabetic for 4 years, September 8 1943, found unconscious, perspiring profusely and unresponsive, transferred to hospital. ‘The patient became quite unruly and violent, struggling constantly, having to be restrained, and pulled out the intravenous needle after only 300cc of 5% glucose had been administered.’ There was no change in the clinical course during the interval except that the patient screamed irrationally at times.’ ‘Thereafter the Patient improved and apparently had an uneventful course after proper regulation of his diabetes.’
Case 2 – 55 year old white male, diabetic since 1938, was admitted to st Paul’s Hospital in diabetic coma on February 13th 1945 at 12 noon having been found unresponsive at 10.00 am, but was alright at 7am. 10% glucose solution was started intravenously immediately upon his arrival and was continued until the patient had received 4000cc by 10.45pm. The Patient remained semi comatose on March 1st until 9.00pm at which time he appeared very restless, got out of bed, struggled with the nurses, and had alternating intervals of crying out irrationally and of being quiet. The patient remained about the same until the 16th March when he became weaker, his temperature began rising, and signs of pneumonia appeared in the lungs. He died on March 18th at 8.20pm.
Case 3 – 7 year old white male, diabetic since January 1943, admitted to Baylor University hospital at 4.30pm on September 27 1945 following convulsions. As the patient continued to have convulsions and was comatose it was decided to bring the child to Dallas. The patient was admitted to hospital upon arrival.’ The patient was given 70cc of 50% glucose and 1000cc of 10% glucose intravenously. At 6.00pm on September 28th, respirations ceased permanently.’ The patient died.
Clinically cases of post hypoglycaemia encephalopathy have been reported in every age group, as frequent in children as in adults.
‘Darrow had 2 cases of convulsions and mental deficiency in children following hypoglycaemia.’ Another similar case with coma for 17 days terminating in death reported by Lawrence et al.
It is recommended that the term post hypoglycaemic encephalopathy be used for this very definite clinical entity. Members of the medical profession should be aware of this very serious complication of hypoglycaemia and combat any prolonged low blood glucose level vigorously.
15) Patients who carefully Manage Diabetes May Face Hidden Risks, By James s Hirsch, Wall Street Journal 29.6.1996. This describes a 26 year old insulin dependent diabetic nurse, two months pregnant, who following diabetic coma, lost control of her car which battered off the road and crashed into a tree, killing her. Authorities estimate she was travelling at 73 miles per hour and there was no skid marks. She passed out and her foot hit the accelerator. Research studies estimate that between 4% and 13% of the insulin dependent diabetic patients who die each year perish in hypoglycaemia related accidents.
16) Human Insulin – A Decade of Experience and Future Developments – Diabetes Care Dec 1993
17) Report to BDA Low Task Force – 1992
18) Human Insulin Advice – Forest & Evans 1992
19) Hypoglycaemia Unawareness in Diabetics Transferred from Beef / Porcine Insulin to Human Insulin – A. Teuscher; W D Berger, The Lancet August 15 1987
20) Human insulin and unawareness of hypoglycaemia: need for a large randomised trial – Egger, Smith, Teuscher, BMJ August 1992
21) The Diabetes Handbook – Day, BDA 1986
22) DCCT Diabetes Control and Complications Trial – 1993
23) Bellagio Report – 1996
24) Diabetes & cognitive function: the evidence so far – A British Diabetic Association Report November 1996
25) Hypoglycaemia in insulin requiring diabetes – A patient and carer perspective – IDDT 1997
26) Cochrane Review – ‘Human’ insulin versus animal insulin in people with diabetes mellitus – Richter, Neises 2002
27) INSULIN – A Voice for Choice by Professor Arthur Teuscher, Karger 2007
28) 30 YEARS OF SYNTHETIC INSULIN, ARE PEOPLE WITH DIABETES GETTING THE BEST DEAL? A report of patient’s concerns IDDT 2007
29) Diabetes in Scotland 2013