Newer techniques to study neonatal hypoglycemia

Newer Techniques to Study Neonatal Hypoglycemia Anne Kinnala, Heikki Korvenranta, and Riitta Parkkola

Severe neurological sequelae may occur after symptomatic neonatal hypoglycemia. New neuroimaging techniques allow both structural and functional detection of these disturbances. The new diagnostic modalities have shown also transient structural findings associated with neonatal hypoglycemia. The prognostic value of these techniques remains still obscure. Copyright 9 2000 by W.B. Saunders Company ypoglycemia is a c o m m o n metabolic abnormality in newborn infants. Blood glucose m e a s u r e m e n t s and histopathologically docu m e n t e d brain d a m a g e have b e e n m e t h o d s to study hypoglycemia a n d its consequences. 1-4 Newer techniques such as c o m p u t e r tomograplay (CT), magnetic resonance imaging (MRI), and positron emission t o m o g r a p h y (PET) allow structural a n d dynamic functional evaluation of hypoglycemia in infants.

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Computer T o m o g r a p h y and Magnetic R e s o n a n c e Imaging T h e fast d e v e l o p m e n t of high-resolution tomographic imaging during the past 20 years has had a significant impact on the diagnosis and m a n a g e m e n t of neonatal neurological disorders. 5 MRI is probably the most sensitive a n d specific imaging technique for examination of neonates with suspected brain injury. MRI is superior to b o t h ultrasound and CT as to the resolution. MRI gives also a clear differentiation between gray a n d white matter and delineation of the progression of m y e l i n a t i o n - - t h e 2 m a j o r features of n o r m a l neonatal brain development. Thus, MRI has i m p r o v e d our possibility to diagnose metabolic a n d neurodegenerative disorders. Importantly, MRI does not expose the neonate to radiation. 6 C o m p a r e d with adults, the neonatal brain contains a higher p r o p o r t i o n of water (92% to 95% v 82% to 85%). 7 This makes the T1 and T2 From the Depmtments of Pediatrics and Diagnostic Radiology, University of Tu~ku, FIN-20520 Turku, Finland. Address rep~int requests to Anne Kinnala, MD, Department of Pediatrics, University of Turku, FIN-20520 Turku, Finland. Copyright 9 2000 by W.B. Saunders Company O146-0005/00/2402-000.4510. 00/0 doi: 10.1053/sp. 2000. 6362

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values of the neonatal brain m u c h longer than of adults. With increasing age, the water content of the brain decreases and reaches adult levels in children 2 to 5 years of age. T h e change in the differentiation between gray and white m a t t e r is attributed to the relatively greater loss of water f r o m the white matter. In addition, myelin is being deposited in white matter, which f u r t h e r accentuates tissue differences. T h e progression of myelination correlates also with gestational age a n d is reflected in the age-related increase in brain cholesterol content. T h e myelination of tracts in the brain appears to c o r r e s p o n d to functional maturity. 8 Depression of myelin as imaged by MRI has correlated well with measurements of local glucose metabolism d e m o n strated by PET, an indicator of functional activity. 9 T h e infantile pattern is typically p r e s e n t before birth and for the first 8 m o n t h s following birth. It is characterized by a reversal o f the n o r m a l adult pattern on T2-weighted images. MRI is valuable in the examination of the pediatric brain because it does not use ionizing radiation, 1~ and because it provides excellent contrast between gray and white matter, u,12 T h e superiority of MRI over ultrasonography in detecting n o n h e m o r r h a g i c p a r e n c h y m a l brain inj u r y is well known. 6 T h e histopathological findings of neonatal hypoglycemia are well recognized, ~,4 but studies of imaging of the brain of infants with neonatal hypoglycemia are few. Neonatal hypoglycemia is associated with generalized cortical thinning, which is most p r o m i n e n t in the occipital lobes, as d e m o n s t r a t e d by c o m p u t e d t o m o g r a p h y a n d MRI. 13'14 Spar et al 1-~ p r e s e n t e d CT and MRI findings of 1 infant, who had had severe hypoglycemia for 15 hours, at age 19 days and observed progressive p a r e n c h y m a l loss a n d predominantly occipital involvement. A n o t h e r MRI

Seminars in Perinatology, Vol 24, No 2 (April), 2000: pp 116-119

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r e p o r t on a hypoglycemic infant at the ages 10 days and 4 months showed diffuse parenchymal loss and hypointense areas resembling infarction in both occipital regions and dilatation of the occipital horns o f the lateral ventricles. At the age of 4 months there was atrophy of the occipital cortex. 15 T h e authors postulated that selective occipital vulnerability may be related to intense axonal migration and synaptogenesis which occurs within the occipital lobes during the neonatal period. Barkovich et a114 have rep o r t e d 5 infants who suffered severe and prolonged hypoglycemia during the neonatal period. In each infant, the d o m i n a n t pattern of injury involved cortical and subcortical regions, mainly within the occipital and parietal lobes. These 3 reports recognize that severe and prolonged neonatal hypoglycemia may result in significant patterns of cerebral injury. In another recent study of hypoglycemic infants no such severe abnormalities were found, when hypoglycemia was adequately treated. 16 MRI detected only m i n o r abnormalities. Structural changes in the brain of infants were investigated in 18 infants after symptomatic neonatal hypoglycemia and in 19 healthy newborn bab i e s / 6 The cranial MRI and ultrasonography (US) examinations were d o n e both at full-term and at the corrected gestational age of 2 months. T h e neurologic o u t c o m e was followed in both groups for 5 to 12 months. Seven of 18 hypoglycemic infants (39%) had abnormal MRI a n d / o r US examinations either in the neonatal period or at the age o f 2 months. Four infants had patchy hyperintensive lesions either in the occipital periventricular white matter or in the thalamus on Tl-weighted images (Fig 1). One of these four infants had also hyperechogenic areas in the periventricnlar white matter, which was interpreted as leucomalasia at full-term age. In addition, 2 babies had unilateral dilatation of lateral ventricles. Most of these lesions were transient. Thirty-three percent (2/6) of the hypoglycemic small for gestational age children had abnormalities in either the MRI or the US imaging findings. The d e v e l o p m e n t of the hypoglycemic children was followed up and the m e a n follow-up time was 11 months (range, 5 to 12 m o n t h s until now and follow-up will continue). So far, only 1 of these infants with abnormal MRI findings has developed right sided hemiplegia. Both of MRI examinations showed abnormali-

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Figure 1. Coronal Tl-weighted images of the occipital white matter. (A) Normal signal intensity of the white and grey matter of the occipital region in the healthy newborn. (B) Patchy hyperintensities (arrow) on the left occipital white matter in the brain of a baby with transient neonatal hypoglycemia.

ties, but the infant's first cerebral US scan at age 6 days was normal.

Positron Emission Tomography PET with 2@8F]Fluoro-2-deoxy-D-glucose (FDG) as the tracer is a noninvasive imaging technique, which enables determination of the regional glucose metabolism in the h u m a n brain. 17,1s A positron emitting tracer is administered and

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PET is used to detect the incident p h o t o n pairs created in the annihilation reaction between positrons and tissue electrons. The photons are r e c o r d e d externally by a circular array of scintillation detectors and the spatial distribution of the radioactivity within the tissue can be quantified in reconstructured images. Thus, PET can be used to measure local tracer concentrations in various body organs noninvasively. The short half-life of positron emitting radionuclides (for 18F T1/2 109 minutes) allows relatively large amounts o f radioactivity to be administered, while minimizing the absorbed radiation. FDG is widely used for determining cerebraP 9 and muscular glucose utilizationY ~ FDG, like glucose, is transported across the blood-brain barrier by the hexose carrier and phosphorylated by hexokinase but, unlike glucose, is unable to be metaboli,zed further along the glycolytic pathway, and the radioactive label is trapped in the tissue. 21 T h e quantification o f the regional glucose metabolism by PET with FDG requires knowledge of the differences in transport of FDG and glucose across the blood-brain-barrier, as well as the affinity to the hexokinase in the first step of the glycolysis. These differences are taken into account with a correction term called the lumped constant (LC). 17,1s The LC is relatively stable under normoglycemic physiological conditions. 17 However, the LC changes in hypoglycemic or hyperglycemic states. 22 T h e LC has been determined experimentally in adults, m,23 T h e value of the LC of infants is not known. In newborn infants the LC may differ greatly from normal adult values. Furthermore, the value of the LC may vary markedly in ischemic and infarcted tissue and during hypoglycemia and hyperglycemia. 22 LC o f 0.52 has been measured for the brain of young adults. 21 Theoretically, the effect of using a LC that is artificially low or high is to increase or decrease the calculated LCMRglc values. T h e r e p o r t e d LC value for the brain has risen from 0.42 to 0.82 over the yearsA s.2~ Quantification o f the cerebral glucose metabolism by PET in children is also associated with other special problems. Fixation of the head for the study requires special holders p l a n n e d for newborn infants. T h e examinations are per, f o r m e d during the postprandial sleep, without sedation. T h e model for calculation of the glucose c o n s u m p t i o m r e q u i r e s knowledge of arterial FDG concentrations. To minimize blood sampling, the c o m b i n e d curves of the activity concentration within the left cardiac ventricle

during the 5 first minutes of the study and 2 to 10 venous whole blood samples during the rest of the study have been used. 24 For ethical reasons, arterial sampling is not possible in neonates or infants. Eight newborn infants with symptomatic hypoglycemia were studied with FDG-PET. O f these 8 babies, 6 were infants of diabetic mothers, 4 were preterm. 25 In addition, 1 infant was p r e t e r m and a n o t h e r infant was small for gestational age. The LCMRglc of these infants were c o m p a r e d with the values of 8 babies who had suspected hypoxic-ischemic brain injury and who were normoglycemic at birth and had normal neurological development during the follow-up. T h e development of the infants was carefully evaluated clinically for a follow-up time of 12 to 36 months. The PET studies were perf o r m e d at the age of 5.3 _ 6.2 days during normoglycemia. No episodes of hypoglycemia occurred during the study periods. T h e plasma glucose concentrations did not differ significantly during the PET study between the hypoglycemic infants and the control group. T h e m e a n LCMRglc of the whole brain did not differ significantly between the hypoglycemic and control infants. The LCMRglc of the whole brain was 4.9 + 2.1 / z m o l / 1 0 0 g / m i n and 7.2 + 1.8 /xmol/100g/min, respectively. T h e r e was no significant difference in either the cerebellar LCMRglc or the LCMRglc of the frontal, temporal and occipital cortex. T h e average values o f the MRglc in the frontal, temporal, and occipital cortex did not differ significantly between the hypoglycemic and the control groups. The skeletal muscle glucose utilization was similar in the hypoglycemic a n d control infants, 6.3 + 2.8 /~mol/100g/min and 8.0 + 2.8 # m o l / 1 0 0 g / rain, respectively. 2~ T h e measured LCMRglc values are in agreem e n t with earlier studies with 18-FDG and PET. 5,9,25,26 During the first year, the cerebellar LCMRglc is close to adult rates, 17.6 /~mol/ 100g/min. 26 The LCMRglc of the cerebellum in this study ( 1 1 / z m o l / 1 0 0 g / m i n ) was lower. However, the patients in this study were younger than those reported in previous studies. T h e LCMRglc changes during brain d e v e l o p m e n t and in the newborn infants it is highest in the sensorimotor cortex, thalamic nuclei, brainstem, and cerebellar vermis. 9'26 Relatively low values have b e e n r e c o r d e d in the frontal areas and striatal regions. The pattern of maturation of the

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cerebral cortical and subcortical glucose uptake was normal also in this study. A decrease of LCMRglc of 40% has been found during hypoglycemia in adultsY 7 It has been shown in s o m e , 28,2~ but not all studies, s~ that glucose transport over the blood-brain-barrier is subject to adaptation during abnormal levels of glycemia in animals/1 The adaptation of the glucose transport of the brain to control rates may take 5 to 25 days after normoglycemia is achieved/9 Most of these hypoglycemic infants were infants of diabetic mothers. 25 Maternal hyperglycemia produces fetal hyperglycemia and stimulates fetal insulin secretion. ~2 Abnormal glucose levels during pregnancy could lead to altered glucose transport over the fetal bloodbrain-barrier. Differences between the results of this study and those of Blomqvist et a127 and McCall et a129 may be related to differences in the duration and severity of the hypoglycemia.

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