Neonatal Hypoglycemia

096_Valk_Neonatal_Hypoglyc 08.04.2005 16:55 Uhr Seite 749 Chapter 96 Neonatal Hypoglycemia R.J.Vermeulen, J.Valk 96.1 Clinical and Laboratory Findings ronal damage and histochemical differences. Hypo- glycemia leads to reduced concentrations of pyruvate Neonatal hypoglycemia is a condition that frequently and lactate and diminishes the production of protons occurs in sick newborns. The symptomatology in the by the Krebs cycle, resulting in tissue alkalosis, while acute stage can range from agitation, somnolence, hypoxia–ischemia is characterized by elevated lactate and epileptic seizures to status epilepticus and coma. and acidosis. In contrast to hypoxia–ischemia, hypo- Several groups of neonates are at risk of hypoglycemia does not lead to pannecrosis,but to selective glycemia because of a lack of glucose reserves (dys- neuronal necrosis. This neuronal necrosis involves maturity and prematurity) or an increased need for the cerebral cortex, the hippocampus, the caudate glucose related to high weight and maternal diabetes. nucleus,and sometimes the spinal cord.In contrast to The causes of severe neonatal hypoglycemia are hypoxia–ischemia, the brain stem and the cerebellum diverse and can be separated in three large groups: are spared in hypoglycemia. In addition, the cortical hyperinsulinism (Beckwith–Wiedemann syndrome, neuronal necrosis is more superficial in hypo- nesidioblastosis–adenoma spectrum, hyperplasia of glycemia, whereas the middle cortical layers are pref- the pancreas, leucine sensitivity), endocrine deficien- erentially targeted by hypoxia–ischemia. Axon-spar- cies (cortisol deficiency, growth hormone deficiency, ing parenchymal lesions with selective dendritic glucagon deficiency, hypothyroidism, panhypopitu- swellings are often considered a hallmark of hypo- itarism), and hereditary metabolic defects (defects in glycemic damage. These swollen dendrites contain carbohydrate, amino acid, organic acid, and fatty acid swollen mitochondria. In the next phase swollen mi- metabolism). tochondria are seen in the cell body and cell mem- Long-term outcome of infants with severe neona- brane irregularities appear. Finally, the neurons be- tal hypoglycemia varies from fatal, through poor with come necrotic, as indicated by mitochondrial floccu- severe mental retardation, epilepsy, and visual im- lent densities and frank membrane rupture. There is pairment, to absence of evident neurological conse- a free admixture of amorphous cytoplasm within the quences. Visual impairment is an important clinical extracellular space, indicating cellular dissolution. manifestation of neonatal hypoglycemia and results The cytoplasm of the affected cells stains acidophilic from the preferential damage of the parieto-occipital in light microscopy. The dendritic death of neurons is white and gray matter. In addition, optic atrophy has characteristic of excitotoxicity. been described, most probably secondary to the le- Neuropathological observations of damage to the sions in the parieto-occipital region through the neonatal brain in pure hypoglycemia are limited. In mechanism of transsynaptic degeneration. the few studies of untreated or inadequately treated It should be noted that there is no consensus about hypoglycemic neonates, involvement of all parts of the exact definition of hypoglycemia. It has been the brain and the anterior horns of the spinal cord has shown that even moderate hypoglycemia is a poten- been observed, with particularly severe lesions in the tial hazard for the neonatal brain. For instance, glu- posterior parts of the cerebrum, the parieto-occipital cose levels below 2.6 mmol/l can be associated with lobes.Involvement of arterial border zones,as may be motor and cognitive impairment. Deterioration of seen in hypoxic–ischemic encephalopathy, is not motor and cognitive skills is not only related to the seen. As in adults, cortical involvement includes the depth of the hypoglycemia, but also to the number of superficial cortical layers and not the deeper layers as days with hypoglycemic episodes. in hypoxia–ischemia.Microscopically the findings in- clude acute degeneration of nerve cells and glial cells. In most infants the nerve cells in the cortex are small 96.2 Pathology with abnormal nuclei.There is a regional distribution of neuronal damage, with the most severe signs of Most data on hypoglycemic brain damage have been acute degeneration in the occipital cortex and the obtained in adults.In human adults it is often difficult least signs of involvement in the temporal cortex. to distinguish hypoglycemic from hypoxic–ischemic Fragmented cells may be demonstrated in the caudate brain damage on morphological grounds. There nucleus and putamen, the claustrum, and the granu- are, however, differences in distribution of the neu- lar layer of the cerebellum.Another type of damage is 096_Valk_Neonatal_Hypoglyc 08.04.2005 16:55 Uhr Seite 750 750 Chapter 96 Neonatal Hypoglycemia found in large neurons (thalamus, hypothalamus, rate of the brain does not change, in contrast to under globus pallidus, and Purkinje cells) showing chroma- conditions of hypoxia–ischemia, where the metabolic tolysis with swelling and granularity of the cyto- rate decreases. A difference between the posterior plasm. Large vacuoles may be observed in the motor part and the rest of the brain has, however, not been nuclei of the brain stem. demonstrated. Low glucose levels lead to a reduction of energy supply and to protein and lipid catabolism.Because of 96.3 Pathogenetic Considerations the lower glucose levels, levels of lactate and pyruvate are also reduced. Consequently proton production by Hypoxia–ischemia and hypoglycemia both lead to the Krebs cycle is reduced, leading to tissue alkalosis, energy failure, and one would expect similar patterns in contrast to ischemia, which is characterized by ele- of brain damage. There are, however, major differ- vated levels of pyruvate and lactate and acidosis. In ences, especially well known from the patterns of hypoglycemia decarboxylation of pyruvate is de- brain damage following perinatal asphyxia and creased, leading to a shortage of CoA, a major inter- neonatal hypoglycemia. Only in neonatal hypo- mediate in the pathway to oxaloacetate. Oxaloacetate glycemia is preferential damage of the parieto-occip- is the a-keto acid in a transamination reaction with ital region seen. The differences require an explana- glutamate, yielding aspartate and a-ketoglutarate. tion. Shortage of oxaloacetate subsequently leads to a re- The immature brains of neonates have the facility duction of tissue glutamate and an increase in aspar- to use alternative energy donors (for instance lactate tate. This increase in the aspartate/glutamate ratio is and ketone bodies), an ability that gradually disap- the reverse of what is seen in hypoxic–ischemic con- pears with age. This and the lesser energy demand of ditions.Aspartate is more selectively active on NMDA the neonatal brain explain why the immature brain is receptors than glutamate. NMDA antagonists are, at more resistant to hypoglycemia than more mature least in experimental situations, more effective in hy- brains. This is probably the reason why hypoglycemic poglycemia than in hypoxia–ischemia. However, no brain damage rarely occurs in neonates without a pattern of distribution of NMDA receptors is known predisposing factor. Glucose utilization in newborns that would explain the vulnerability of the posterior as measured with 2-deoxy-2-[17F]fluoro-D-glucose part of the cerebral hemispheres in neonates. PET does not demonstrate a higher glucose turnover Delivery of glucose to the brain requires so-called in the occipital cortical area than in other cortical ar- glucose transporter proteins. Endothelial cells play a eas. crucial role in the transport of glucose over the blood Neuronal death by hypoxic–ischemic energy de- -brain barrier since they are equipped with GLUT1 pletion includes instant cell death and delayed cell glucose transporters. In addition, GLUT3, a neuronal damage and death, the latter mediated by a cascade of glucose transporter, shows a developmental regula- events including membrane depolarization, calcium tion of expression, at least in the newborn rat. How- influx into the cytosol, release of proteases and lipas- ever,it has not been reported that this transporter has es, formation of free radicals, lipid fragmentation and a regional distribution that would explain the selec- formation of arachidonic acid, and lipid peroxida- tive vulnerability of the parieto-occipital region. tion. Brain damage in hypoglycemia is not the direct The GLUT5 transporter is selectively expressed in mi- and immediate result of the lack of glucose, but fol- croglia, whereas the other types of glucose trans- lows the steps of delayed cell death. It has been suggested that one of the important differences between hypoxic–ischemic and hypoglycemic conditions concerns the cerebral blood flow. ᮣ The two- to threefold increase in cerebral blood flow Fig. 96.1. A male neonate suffered from severe and repeated that occurs in patients with hypoglycemia is then as- hypoglycemia. This first MRI was obtained at the age of 16 sumed not to occur in hypoxia–ischemia. This, how- days. The T2-weighted images (first and second rows) show ever, is not true in all cases of hypoxia–ischemia, blurring of the cortical ribbon in the parieto-occipital and tem- where an initial rise in cerebral blood flow of the poral areas and swelling of these areas.The signal intensity of same order may

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