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Chapter 96 Neonatal

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, –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 hypo- glycemia does not lead to pannecrosis,but to selective glycemia because of a lack of reserves (dys- neuronal necrosis. This neuronal necrosis involves maturity and prematurity) or an increased need for the , 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 stem and the 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- ). tochondria are seen in the cell body and cell mem- Long-term outcome of infants with severe neona- brane irregularities appear. Finally, the be- tal hypoglycemia varies from fatal, through poor with come necrotic, as indicated by mitochondrial floccu- severe mental retardation, , 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 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 hypo- glycemic 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 occur, followed by a decrease when the is too high for normal unmyelinated white generalized hypoxia–ischemia also affects the cardiac matter in these regions,suggesting edema.There is also a high muscle. The cardiac muscle seems more resistant to signal intensity in the peripheral parts of the cerebellar hemi- low glucose levels than to hypoxia–ischemia. This dif- spheres,which is extremely unusual in post-hypoxic–ischemic

ference could be important. Correction of the hypo- encephalopathy. The T1-weighted images (third and fourth glycemia leads to a decrease in cerebral blood flow to rows) show areas of cortical laminar hyperintensity in the values about 30% below normal. PET studies reveal frontal and parietal areas and loss of gray–white matter dis- that under hypoglycemic conditions the metabolic tinction in the posterior parieto-occipital and temporal area 096_Valk_Neonatal_Hypoglyc 08.04.2005 16:55 Uhr Seite 751

96.3 Pathogenetic Considerations 751

Fig. 96.1. 096_Valk_Neonatal_Hypoglyc 08.04.2005 16:55 Uhr Seite 752

752 Chapter 96 Neonatal Hypoglycemia

Fig. 96.2. Diffusion-weighted imaging was performed in the minent in the parieto-occipital area, but also in both frontal same boy at 16 days. The Trace diffusion-weighted (b = 1000) and temporal lobes. The ADC maps (second row) confirm the images (first row) show extensive hyperintensities, most pro- severe restriction in water diffusion in the affected areas

porters (2, 4, and 7) are only expressed at very low glycemia should be avoided because of the risk of levels in the brain. neurological complications. After correction of the So none of the factors mentioned above would ex- hypoglycemia, tapering of intravenous glucose infu- plain either the selective involvement of the parieto- sion should be slow in order to avoid secondary hypo- occipital gray and white matter in neonates or the glycemia. In addition, treatment of any specific caus- sparing of the cerebellum and brain stem. es underlying the hypoglycemia, including endocrine dysfunction and inborn errors of metabolism, should be instituted as appropriate. 96.4 Therapy

Prevention is the most important form of treatment. 96.5 Magnetic Resonance Imaging It is essential to identify infants at risk of hypo- glycemia and to detect the first signs of its occur- The standard protocol used for preterm and term rence. Special risk factors have been discussed above. neonates, described in Chap. 95, is also appropriate In the postnatal period maintenance of body temper- for imaging hypoglycemic brain lesions. This proto- ature, oral feeding within 3–4 h after birth and moni- col includes T1-weighted, proton density, and T2- toring the clinical signs of hypoglycemia (jitteriness weighted images for morphological and pathomor- and seizures) are important in the prevention and phological information. Gradient echo refocused im- early detection of hypoglycemia. Even in neonates ages are used to detect hemorrhagic components and with only mildly low glucose levels, treatment should calcifications. In addition diffusion-weighted Trace be initiated,starting with a bolus infusion followed by images and ADC maps should be obtained, to reveal a continuous glucose infusion. Importantly, hyper- the extent of damage and to discover abnormal 096_Valk_Neonatal_Hypoglyc 08.04.2005 16:55 Uhr Seite 753

96.5 Magnetic Resonance Imaging 753

Fig. 96.3. This series of FLAIR images, obtained at 21 days in The underlying white matter has become dark, suggesting the same boy, confirm the extensive cortical involvement. On- white matter degeneration and rarefaction ly the most anterior part of the frontal cortex seems spared.

areas with a normal appearance on conventional se- dark (Fig. 96.3), compatible with ongoing cortical quences. Where available, MRS should be part of the necrosis and white matter degeneration and rarefac- examination. tion. Soon macrocysts develop, the cysts extending The most constant finding on MRI in early hypo- from cortex to ventricular wall (Fig. 96.4). The cortex glycemic encephalopathy consists of hyperintense covering these cysts is extremely thin. However, the and swollen areas on proton density,T2-weighted,and initial hypoglycemic brain lesions are reversible in FLAIR images, predominantly located in the parieto- some cases or are reversible in part of the brain (com- occipital lobes (Fig. 96.1). The lesions tend to be more pare Figs. 96.2 and 96.4). In the final stages MRI or less symmetrical and may involve the splenium of shows tissue loss, especially of the white matter, with the corpus callosum. T1-weighted images may show crowding of the overlying gyri (ulegyria) in the pari- linear high-signal changes in the depth of the cortical eto-occipital region. Usually the trigonum and occip- sulci, in particular in the parieto-occipital areas ital horns of the lateral ventricles are dilated. (Fig. 96.1). After intravenous gadolinium the latter MRS should show low concentrations of lactate in abnormalities may become more conspicuous. In the the initial lesions, in contrast to what is seen in peri- initial phase the affected areas show high signal in- natal asphyxia. MR phosphorus spectroscopy is able tensity on diffusion-weighted Trace images and ADC to confirm the alkalosis in hypoglycemia versus the values are decreased by about 25–40% compared to acidosis in hypoxia–ischemia. normal (Fig. 96.2).Very low ADC values (0.50–0.70) of The differential diagnosis in the early phase of hy- the affected parieto-occipital lobes suggest irre- poglycemia includes only a few other disease states. versible cytotoxic edema leading to permanent loss of The most prominent is bilateral occlusion of both brain tissue. Follow-up FLAIR images show cortical posterior cerebral arteries, as may occur in patients hyperintensity, whereas the white matter becomes with preceding severe brain edema. The P3 segment 096_Valk_Neonatal_Hypoglyc 08.04.2005 16:55 Uhr Seite 754

754 Chapter 96 Neonatal Hypoglycemia

Fig. 96.4. This series of T1-weighted images was obtained rhagic. Note that not all areas with severe diffusion restriction in the same boy at 6 weeks.There is multicystic degeneration underwent the same degeneration of both parieto-occipital lobes. The lesions are partly hemor-

of the posterior cerebral artery may be compressed ischemic damage is often present in hypoglycemia, against the tentorial ridge and bilateral posterior ter- which may make the hypoglycemic damage pattern ritorial infarctions may result. Concurrent hypoxic– less clear.