2. Introduction
• This condition is now relatively infrequent but is an important cause
of confusion, convulsions, stupor, and coma; as such, it merits
separate consideration as a metabolic disorder of the brain.
• The essential biochemical abnormality is a critical lowering of the
blood glucose.
3. Contd....
• At a level of about 30 mg/ dL, the cerebral disorder takes the form of a
confusional state and one or more seizures may occu.
• At a level of 10 mg/dL, there is coma that may result in irreparable injury to
the brain if not corrected immediately by the administration of glucose.
• As with most other metabolic encephalopathies, the rate of decline of blood
glucose is a factor in both the depression of consciousness and residual
dementia.
4. Contd....
• The normal brain has a glucose reserve of 1 to 2 g (30 mmol/100 g of
tissue), mostly in the form of glycogen.
• Because glucose is utilized by the brain at a rate of 60 to 80 mg/min,
the glucose reserve may sustain cerebral activity for 30 min or less
once blood glucose is no longer available.
5. Contd....
• Glucose is transported from the blood to the brain by an active carrier
system.
• Glucose entering the brain either undergoes glycolysis or is stored as
glycogen.
• During normal oxygenation (aerobic metabolism), glucose is
converted to pyruvate, which enters the Krebs cycle; with anaerobic
metabolism, lactate is formed.
6. Contd....
• The oxidation of 1 mole of glucose requires 6 mole of 02.
• Of the glucose taken up by the brain, 85 to 90 percent is oxidized;
• the remainder is used in the formation of proteins and other
substances, notably neurotransmitters and particularly GABA.
7. Contd....
• When blood glucose falls, the CNS can utilize nonglucose substrates
to a variable extent for its metabolic needs, especially keto acids and
intermediates of glucose metabolism, such as lactate, pyruvate,
fructose, and other hexoses.
8. Contd....
• In the neonatal brain, which has a higher glycogen reserve, keto acids
provide a considerable proportion of cerebral energy requirements;
this also happens after prolonged starvation.
• However, in the face of severe and sustained hypoglycemia, these
alternative substrates are inadequate to preserve the structural
integrity of neurons, and eventually ATP is depleted as well.
9. Contd....
• If convulsions occur, they usually do so during a period of confusion;
• the convulsions have been attributed to an altered integrity of
neuronal membranes and to elevated NH3 and depressed GABA and
lactate levels.
10. Contd....
• The brain is the only organ besides the heart that suffers severe
functional and structural impairment under conditions of severe
hypoglycemia.
• Beyond what is described above, the pathophysiology of the cerebral
disorder has not been fully elucidated.
11. Contd....
• It is known that hypoglycemia reduces 02 uptake and increases
cerebral blood flow.
• As with anoxia and ischemia, there is experimental evidence that the
excitatory amino acid glutamate is involved in the process.
12. Contd....
• The levels of several brain phospholipid fractions decrease when
animals are given large doses of insulin.
• However, the suggestion that hypoglycemia results in a rapid
depletion and inadequate production of high-energy phosphate
compounds has not been corroborated; some other glucose-
dependent biochemical processes must be implicated.
13. Etiology
• The most common causes of hypoglycemic encephalopathy are:
accidental or deliberate overdose of insulin or an oral diabetic agent
islet cell insulin-secreting tumor of the pancreas
depletion of liver glycogen, which occasionally follows a prolonged
alcoholic binge, starvation, or any form of severe liver failure
glycogen storage disease of infancy;
14. Contd....
an idiopathic hypoglycemia in the neonatal period and infancy
subacute and chronic hypoglycemia from islet cell hypertrophy and
islet cell tumors of the pancreas, carcinoma of the stomach, fibrous
mesothelioma, carcinoma of the cecum, and hepatoma.
• Purportedly, an insulin-like substance is elaborated by these
nonpancreatic tumors.
15. Contd....
• In functional hyperinsulinism, as occurs in anorexia nervosa and
dietary faddism, the hypoglycemia is rarely of sufficient severity or
duration to damage the CNS.
16. Clinical Features
• The initial symptoms appear when the blood glucose has descended
to about 30 mg/dL, nervousness, hunger, flushed facies, sweating,
headache, palpitation, trembling, and anxiety.
• These gradually give way to confusion and drowsiness or occasionally,
to excitement, overactivity, and bizarre or combative behavior.
17. Contd....
• Many of the early symptoms relate to adrenal and sympathetic
overactivity and some of the manifestations may be muted in diabetic
patients with neuropathy.
• In the next stage, forced sucking, grasping, motor restlessness,
muscular spasms, and decerebrate rigidity occur, in that sequence.
18. Contd....
• Myoclonic twitching and convulsions develop in some patients.
• Rarely, there are focal cerebral deficits, the pathogenesis of which
remains unexplained;
• according to Malouf and Brust, hemiplegia, corrected by intravenous
glucose, was observed in 3 of 125 patients who presented with
symptomatic hypoglycemia.
19. Contd....
• Blood glucose levels of approximately 10 mg/dL are associated with
deep coma, dilatation of pupils, pale skin, shallow respiration, slow
pulse and hypotonia,
• what had in the past been termed the "medullary phase" of
hypoglycemia.
20. Contd....
• If glucose is administered before this level has been attained, the
patient can be restored to normal, retracing the aforementioned
steps in reverse order.
• However, once this state is reached, and particularly if it persists for
more than a few minutes, recovery is delayed for a period of days or
weeks and may be incomplete as noted below.
21. Contd....
• The EEG is altered as the blood glucose falls, but the correlations are
imprecise.
• There is diffuse slowing in the theta or delta range.
• During recovery, sharp waves may appear and coincide in some cases
with seizures.
22. Contd....
• The major clinical differences between hypoglycemic and hypoxic
encephalopathy lie in the setting and the mode of evolution of the
neurologic disorder.
• The effects of hypoglycemia usually unfold more slowly, over a period
of 30 to 60 min, rather than in a few seconds or minutes.
• The recovery phase and sequelae of the 2 conditions are quite similar.
23. Contd....
• A large dose of insulin, which produces intense hypoglycemia, even of
relatively brief duration (30 to 60 min), is more dangerous than a
series of less-severe hypoglycemic episodes from smaller doses of
insulin, possibly because the former impairs or exhausts essential
enzymes, a condition that cannot then be overcome by large
quantities of intravenous glucose.
24. Contd....
• Reflecting the benignity of repeated minor occurrences, the
Epidemiology of Diabetes Interventions and Complications Study
Research Group have demonstrated that recurrent hypoglycemic
episodes in the course of treatment of diabetes over many years are
very well tolerated and do not lead to cognitive decline.
25. Contd....
• A severe and prolonged episode of hypoglycemia may result in
permanent impairment of intellectual function as well as other
neurologic residua, like those that follow severe anoxia.
• We also have observed states of protracted coma, as well as relatively
pure Korsakoff amnesia.
• However, one should not be hasty in prognosis, for we have observed
slow improvement to continue for 1 to 2 years.
26. Contd....
• Recurrent hypoglycemia from an islet cell tumor may masquerade for
some time as an episodic confusional psychosis or convulsive illness;
diagnosis then awaits the demonstration of low blood glucose or
hyperinsulinism in association with the neurologic symptoms.
• We saw a man in the emergency department whose main complaint
was episodic inability to dial a touchtone telephone and a mild
mental fogginess; he was found to have an insulinoma.
27. Contd....
• Functional or reactive hypoglycemia is the most ambiguous of all
syndromes related to low blood glucose.
• This condition is usually idiopathic but may precede the onset of
diabetes mellitus.
• The rise of insulin in response to a carbohydrate meal is delayed but
then causes an excessive fall in blood glucose, to 30 to 40 mg/ dL.
28. Contd....
• The symptoms are malaise, fatigue, nervousness, headache and
tremor, which may be difficult to distinguish from anxious depression.
• Not surprisingly, the term functional hypoglycemia has been much
abused, being applied indiscriminately to a variety of complaints that
would now be called chronic fatigue syndrome or an anxiety
syndrome.
29. Contd....
• In fact, a syndrome attributable to functional or reactive
hypoglycemia is infrequent and its diagnosis requires the finding of an
excessive reaction to insulin, low blood glucose during the
symptomatic period, and a salutary response to oral glucose.
30. Contd....
• In all forms of hypoglycemic encephalopathy, the major damage is to
the cerebral cortex.
• Cortical nerve cells degenerate and are replaced by microglia cells and
astrocytes.
• The distribution of lesions is similar, although probably not identical
to that in hypoxic encephalopathy.
32. Contd....
• Auer has described the ultrastructural changes in neurons resulting
from experimental hypoglycemia; with increasing duration of
hypoglycemia and EEG silence, there are mitochondrial changes, first
in dendrites and then in nerve cell soma, followed by nuclear
membrane disruption leading to cell death.
33. Contd....
• Severe hypoglycemic cerebral injury causes MRI abnormalities
localized to the (particularily vulnerability areas):
basal ganglia
cerebral cortex
substantia nigra, and
hippocampus
34. Treatment
• Treatment of all forms of hypoglycemia obviously consists of
correction of the hypoglycemia at the earliest possible moment.
• It is not known whether hypothermia or other measures will increase
the safety period in hypoglycemia or alter the outcome.
• Seizures and twitching may not stop with antiepileptic drugs until the
hypoglycemia is corrected.
