To discuss the definition of neonatal hypoglycemia and the pathophysiology of hypoglycemia and its effects on the neonatal brain.
To discuss what is known to date regarding the long-term neurodevelopmental outcome of hypoglycemia in the neonatal period.
Definition of Hypoglycemia Difficulty in determining a significant definition of neonatal hypoglycemia. How do we define significant hypoglycemia? Koh et al. A survey of 36 pediatric textbooks and 178 pediatric consultants produced a range from 1-4 mmol/L
What degree of hypoglycemia is significant?
What is our threshold for treated asymptomatic hypoglycemia?
What levels which will impact on neurodevelopmental outcome?
Koh TTHG, Eyre HA, Aynsley-Green A. Neonatal hypoglycemia: the controversy regarding definition. Arch Dis Child 1988;63:1386-8.
Epidemiological approach - less than 5 th percentile from statistical calculations
Approach based on acute metabolic, endocrine, and neurological function - still inadequate evidence
Approach based on long-term neurologic outcome - still inadequate evidence
“ Critical hypoglycemia” What level of hypoglycemia will impact on long term neurodevelopmental outcome? Lucas A, Morley R, Cole TH. Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. BMJ 1988, 297:831-8 Hypoglycemia at less than 2.6 mmol/L occurred in 433 of 661 preterm infants studied. Strong correlation was found between the number of days with recorded hypoglycemia and reduced mental and motor development scores at 18 months. Duvanel CB, Fawer C-L, Cotting J, et al. Long-term effects of neonatal hypoglycemia on brain growth and psychomotor development in small-for-gestational age preterm infants. J Petiatr 1999, 134;492-8. 73% of the 85 SGA preterm newborns tested had hypoglycemia at < 2.6 mmol/L. Strong correlation was found between recurrent episodes of hypoglycemia and persistent neurodevelopmental and physical growth deficits at 5 years of age.
Glucose and the CNS Many such studies are difficult to perform in human subjects, thus much of this work has been done on laboratory animals.
Normal glucose metabolism
Fetus utilizes both maternal glucose, as well as lactate and amino acids.
Upon birth, there is a mobilization of glycogen and fatty acids.
Doubling of glycogen stores occurs at 36 weeks gestation.
These stores are depleted in first 24 hours of life.
Evolving functional maturity
In 5 week old infants, cerebral glucose utilization (CGU) is greatest in the sensorimotor cortex, thalamus, midbrain-brainstem, and cerebellar vermis.
At 3 months, maximal CGU shifts to parietal, temporal, and occipital cortices and the basal ganglia.
By 8 months, there is incresaed frontal and association region CGU.
Resistance to brain injury The neonatal brain differs with adult brains with the following mechanisms providing increased resistance to brain injury:
Enhanced cerebral blood flow (CBF) and cerebral uptake of glucose
Enhanced ability to use alternate substrates
Decreased requirement for glucose utilization
Preservation of cerebral high-energy phosphates
1. CBF and Glucose uptake Pryds O, Greisen G, Friis-Hansen B. Compensatory incrase of CBF in preterm infants during hypoglycemia. Acta Paediatr Scand 1988, 77:632-7. Human infants can increase CBF by 200% above normal when blood glucose falls < 1.6 mmol/L Mujsce DJ, Christensen MA, Vannucci RC. Regional cerebral blood flow and glucose utilization during hypoglycemia in newborn dogs. Am J Physiol 1989, 256:H1859-66. Similar findings in newborn dogs with glucose concentrations at 1.0 mmol/L. CBF increased 170% in white matter to 250% in the thalamus.
Hernandez MJ, Vannucci RC, Salcedo A, et al. Cerebral blood flow and metabolism during hypoglycemia in newborn dogs. J Neurochem 1980, 35:622-8.
In newborn dogs, hypoglycemia < 1.0 mmol/L resulted in:
a preserved cerebral metabolic rate for oxygen
decrease of glucose metabolism by 50%
lactate metabolism increased 10-fold
4. Stable ATP levels Vannuci RC, Nardis EE, Vannucci SJ, et al. Cerebral carbohydrate and energy metabolism during hypoglycemia in newborn dogs. Am J Physiol 1981, 240:R192-9 Similar investigations showed high energy phosphate (phosphocreatine and ATP) reserves reamined within normal during hypoglycemia in newborn dogs.
Concomitant disorders Hypoglycemia is more deleterious when superimposed on hypoxia-ischemia or seizures, according to animal studies. Vannucci RC, Vannucci SJ. Cerebral carbohydrate metabolism during hypoglycemia and anoxia in newborn rats. Ann Neurol 1978, 4:73-9. In newborn rat pups subjected to anoxia, normoglycemic pups survived 10x longer than hypoglycemic ones. Young RS, Cowan BE, Petrof OA. In vivo 31P and in vitro 1H nuclear magnetic resonance study of hypoglycemia during neonatal seizure. Ann Neurol 1987, 22:622-8. 31P NMR studies showed significant depletion of high-energy phosphate stores when seizures occurred in conjunction with hypoglycemia as compared to without.
Pathological studies of severely hypoglycemic neonatal brains showed:
neuronal injury in cerebral cortex, hippocampus, basal ganglia, thalamus, brainstem, and spinal cord.
neuronal necrosis occurred more than ischemic injury
widespread glial cell degeneration
periventricular leukomalacia in a few cases
Chronic changes :
Pathological studies long after the neonatal period showed:
diffuse loss of neurons in cortex
increase in astrocytes and microglia
calcifications in the necrotic zones
sparing of the cerebellum
Anderson JM, Milner RDG, Strich SJ. Effects of neonatal hypoglycemia on the nervous system: a pathological study. J Neurol Neurosurg Psychiatry 1967, 30:295-310. Banker BQ. The neuropathological effects of anoxia and hypoglycemia in the newborn. Dev Med Child Neurol 1967, 9:544-550.
Spar et al. (1994) were the first to describe neuroimaging changes in neonatal hypoglycemia.
Case report of one infant with symptomatic hypoglycemia at 58 hours of age, with hypoglycemia well-documented at over 15 hours.
MRI at DOL#19 showed:
bilateral occipital lobe parenchymal tissue loss
near complete absence of cerebral cortex in posterior parietal and occipital areas
generalized thinning of the cerebral cortex
No other factors were found to explain this brain damage, and thus was attributed to the hypoglycemic insult.
Spar HA, Lewine JD, Orrison WW. Neonatal hypoglycemia: CT and MR findings. AJNR 1994, 15:1477-1478.
Neuroimaging in hypoglycemia (cont’d) Symptomatic hypoglycemia is associated with parieto-occipital white matter abnormalities, as well as abnormal signals in the deep grey matter structures of the thalamus and basal ganglia. CT image source: Yager JY. Hypoglycemic injury to the immature brain. Clinics in Perinatology 2002, 29:651-674.
Kinnala A, Rikalainen H, Lapinleinu H, Parkkola R, Kormano M, Karo P. Cerebral magnetic resonance imaging and ultrasonography findings after neonatal hypoglycemia. Pediatrics 1999, 103:724-9.
In a study of 18 term infants with symptomatic hypoglycemia:
39% showed MRI or ultrasound abnormalities
4 showed patchy hyperintense lesions on MRI in occipital periventricular white matter or thalamus
3 of 4 did not show these lesions on follow-up MRI
Outcome? Lucas A, Morley R, Cole TG. Adverse neurodevelopmental outcome of moderate neonatal hypoglycemia. BMH 1988, 297:1304-8. Multi-center study of 661 preterm infants weighing < 1850 g, with outcomes determined at 18 months of age. Reduced mental and motor developmental scores were found to be related to increasing number of days with glucose levels < 2.6 mmol/L. Relative risk for neurodevelopmental impairment was 3.5x greater in infants with blood glucose < 2.6 mmol/L for > 5 days.