Patterns of Cerebral Injury and Neurodevelopmental Outcomes After

Symptomatic Neonatal Hypoglycemia

Charlotte M. Burns, Mary A. Rutherford, James P. Boardman and Frances M. Cowan
Pediatrics 2008;122;65
DOI: 10.1542/peds.2007-2822

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ARTICLE

Patterns of Cerebral Injury and Neurodevelopmental

Outcomes After Symptomatic Neonatal Hypoglycemia
Charlotte M. Burns, BSca, Mary A. Rutherford, MD, FRCRb, James P. Boardman, MRCPCH, PhDa,b, Frances M. Cowan, MRCPCH, PhDa,b

aDepartment of Paediatrics, Hammersmith Hospital, Imperial College Healthcare NHS Trust, and bRobert Steiner MR Unit, Imaging Sciences Department, Division of
Clinical Sciences, Imperial College London, London, England

The authors have indicated they have no financial relationships relevant to this article to disclose.

What’s Known on This Subject What This Study Adds

Symptomatic hypoglycemia in the newborn period is associated with long-term neu- Patterns of injury associated with symptomatic neonatal hypoglycemia were more var-
rodevelopmental impairment. ied than described previously. Early MRI findings were more instructive than severity or
duration of hypoglycemia in predicting neurodevelopmental outcomes.

ABSTRACT
BACKGROUND. Symptomatic neonatal hypoglycemia may be associated with later neu-
rodevelopmental impairment. Brain injury patterns identified on early MRI scans
and their relationships to the nature of the hypoglycemic insult and neurodevelop- www.pediatrics.org/cgi/doi/10.1542/
peds.2007-2822
mental outcomes are poorly defined.
doi:10.1542/peds.2007-2822
METHODS. We studied 35 term infants with early brain MRI scans after symptomatic Key Words
neonatal hypoglycemia (median glucose level: 1 mmol/L) without evidence of hy- neonatal hypoglycemia, magnetic
poxic-ischemic encephalopathy. Perinatal data were compared with equivalent data resonance imaging, outcome
from 229 term, neurologically normal infants (control subjects), to identify risk Abbreviations
factors for hypoglycemia. Neurodevelopmental outcomes were assessed at a mini- BGT— basal ganglia/thalami
CP— cerebral palsy
mum of 18 months. DQ— development quotient
GA— gestational age
RESULTS. White matter abnormalities occurred in 94% of infants with hypoglyce- HC— head circumference
mia, being severe in 43%, with a predominantly posterior pattern in 29% of HIE— hypoxic-ischemic encephalopathy
cases. Cortical abnormalities occurred in 51% of infants; 30% had white matter MCA—middle cerebral artery
PLIC—posterior limb of the internal
hemorrhage, 40% basal ganglia/thalamic lesions, and 11% an abnormal posterior capsule
limb of the internal capsule. Three infants had middle cerebral artery territory SI—signal intensity
infarctions. Twenty-three infants (65%) demonstrated impairments at 18 WM—white matter
months, which were related to the severity of white matter injury and involve- Accepted for publication Nov 1, 2007
ment of the posterior limb of the internal capsule. Fourteen infants demonstrated Address correspondence to Frances M.
Cowan, MRCPCH, PhD, Department of
growth restriction, 1 had macrosomia, and 2 had mothers with diabetes mellitus. Paediatrics, Hammersmith Hospital, 5th
Pregnancy-induced hypertension, a family history of seizures, emergency cesar- Floor, Ham House, Du Cane Rd, London,
ean section, and the need for resuscitation were more common among case England W12 0HS. E-mail: f.cowan@
imperial.ac.uk
subjects than control subjects.
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
CONCLUSIONS. Patterns of injury associated with symptomatic neonatal hypoglycemia Online, 1098-4275). Copyright © 2008 by the
American Academy of Pediatrics
were more varied than described previously. White matter injury was not confined
to the posterior regions; hemorrhage, middle cerebral artery infarction, and basal
ganglia/thalamic abnormalities were seen, and cortical involvement was common. Early MRI findings were more
instructive than the severity or duration of hypoglycemia for predicting neurodevelopmental outcomes. Pediatrics
2008;122:65–74

T RANSIENT LOW BLOOD/PLASMA glucose levels are common during the period of metabolic transition to the
extrauterine environment among infants born at term.1,2 In a significant minority, hypoglycemia is associated
with acute neurologic dysfunction, and it has been associated with long-term neurodevelopmental impairment.3,4
The neuroanatomic substrate of injury and its relationships with the severity and duration of hypoglycemia in
humans are unclear; consequently, long-term outcomes are difficult to predict.
There is no universally accepted, “safe” blood glucose level for newborns, partly because individual susceptibility
to brain injury varies, on the basis of factors such as gestational age (GA), type and volume of early milk feedings,
presence of comorbid conditions, and ability of the infant to produce and to use alternative cerebral fuels. In many
centers, this has led to the development of guidelines designed to detect infants at high risk and the implementation
of operational thresholds for intervention, such as those proposed by Cornblath et al.5

PEDIATRICS Volume 122, Number 1, July 2008 65

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 Animal studies and human postmortem studies sug- low-risk term infants recruited from the postnatal ward
gest that severe prolonged hypoglycemia gives rise to at Queen Charlotte’s and Chelsea Hospital in 1996 –
distinct patterns of brain injury, with a propensity for 1997. Those infants were considered neurologically nor-
occipital and parietal cortex and subcortical white matter mal at birth and later16,17 and hereafter are referred to as
(WM) involvement.6–8 This regional susceptibility to oc- control subjects. Prenatal factors recorded were maternal
cipital and parietal WM involvement in hypoglycemic age, race, parity, obstetric history (infertility or multiple
brain injury also has been reported for infants with pregnancy), medical history of systemic disease, any
hypoglycemia,9–15 but studies were limited to small pa- pregnancy-related illness, hypertension (essential or
tient groups, including some infants with hypoxic-isch- pregnancy induced), abdominal pain in the third trimes-
emic encephalopathy (HIE), which confounded image ter, bleeding in any trimester, maternal infection, and
analysis. No study has defined, with a large number of family history of seizures or other neurologic disorders.
infants with symptomatic hypoglycemia but without Perinatal factors recorded were acute intrapartum
HIE, the range of patterns seen on early brain MRI scans, events, maternal intrapartum fever (⬎38°C), epidural or
relating the patterns to clinical presentation and neuro- general anesthesia, induction or augmentation of labor,
developmental outcomes. The aims of this study were to intrapartum complications (shoulder dystocia, cord
document, in term infants with symptomatic neonatal around the neck, or breech presentation), meconium-
hypoglycemia, (1) patterns of brain injury on early MRI stained liquor, mode of delivery, Apgar scores at 1 and 5
scans, (2) any relationship between brain injury and the minutes, and resuscitation measures needed. GA, gen-
documented severity and duration of hypoglycemia, (3) der, birth weight, and head circumference (HC) were
prenatal or perinatal differences between neonates with recorded. The GA and gender were used to determine
hypoglycemia and neurologically normal, low-risk, term the birth weight and HC percentiles from the British
infants, and (4) any relationship between brain MRI growth reference tables. Minor resuscitation was defined
patterns and neurodevelopmental outcomes. as requiring oxygen or intermittent positive pressure
ventilation, and major resuscitation was defined as re-
METHODS quiring intubation (no infant required cardiac compres-
sions or drugs).
Ethical Approval
Ethical approval was obtained from the Hammersmith MRI and Analysis
Hospital Research Ethics Committee. Case subjects underwent MRI as part of the investigation
of their clinical symptoms. They were sedated by using
Patients orally administered chloral hydrate (30 –50 mg/kg). Pa-
Infants who were inborn or were referred to the Ham- rental consent for MRI was obtained. Infants wore ear
mersmith Hospital/Queen Charlotte’s and Chelsea Hos- protection and were monitored by using pulse oximetry
pital and the Robert Steiner MRI unit at the Hammer- and electrocardiography during scanning. An experi-
smith Hospital for MRI between 1992 and 2006, after ⱖ1 enced, MRI-trained neonatologist was in attendance
episode of hypoglycemia, were identified. Study entry throughout the procedure. MRI was conducted by using
criteria were (1) GA of ⬎36 completed weeks at birth, a 1.0-, 1.5-, or 3-T Philips system (Philips Medical Sys-
(2) ⱖ1 documented episode of hypoglycemia (blood or tems, Best, Netherlands), depending on the system being
plasma glucose concentration of ⱕ2.6 mmol/L) associ- used in our unit at the time of presentation. Minimal
ated with acute neurologic dysfunction during the first image acquisition included a T1-weighted sequence in
postnatal week, and (3) MRI at postnatal age of ⬍6 the transverse and sagittal planes and a T2-weighted
weeks. Exclusion criteria were congenital infections, sequence in the transverse plane.
major brain or other malformations, multiple dysmor- All MRI scans were assessed by an experienced neu-
phic features, chromosomal abnormalities, and evidence roradiologist (Dr Rutherford) for anatomic features and
of HIE. abnormal signal intensity (SI). Cortex was described as
Hypoglycemia was defined as stated in criterion 2, appropriate cortical configuration and SI for GA, loss of
and the following factors were recorded: lowest glucose cortical markings, or abnormally high SI on T1-weighted
level, apparent age and mode of presentation, and ap- MRI scans (known as cortical highlighting). WM was
parent duration and nature of any symptoms. Symptoms graded as follows: 0, normal; 1, mild, that is, mildly
included poor feeding, hypothermia, jitteriness, hypoto- increased T1- or T2-weighted MRI SI in the periventricu-
nia, irritability, lethargy, seizures, cyanosis, and apnea. lar or deep WM; 2, moderate, that is, more-marked
Hypoglycemia was classified as brief if it responded to increase in T1- or T2-weighted MRI SI in the periven-
the first intervention and as prolonged/recurrent if it did tricular, deep, or subcortical WM and/or small punctate
not. Hypoglycemia was classified as severe if the lowest hemorrhage; 3, severe, that is, unilateral or bilateral
documented blood/plasma glucose level was ⱕ1.5 overt infarction or a severe focal hemorrhagic lesion.
mmol/L. The nature and location of WM damage also were doc-
umented.
Prenatal and Perinatal Data Basal ganglia/thalami (BGT) was graded as follows: 0,
Data were extracted from the medical notes for all in- normal/mild; 1, moderate/severe (grouped together be-
fants with hypoglycemia. Equivalent data for compari- cause both are associated with the development of cere-
son were available from a well-studied cohort of 229 bral palsy [CP]). Mild indicates focal, possibly transient,

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SI abnormalities, with apparently normal myelination in TABLE 1 Perinatal Characteristics of Case and Control Infants
the posterior limb of the internal capsule (PLIC). Mod- Case (n ⫽ 35) Control (n ⫽ 229)
erate indicates multifocal BGT abnormalities, usually
GA, wk
with abnormal or equivocal PLIC findings. Severe indi-
Median 39.5 39
cates abnormalities of the entire BGT and PLIC. Minimum 37 37
Maximum 42 42
Neurodevelopmental Outcomes Mean ⫾ SD 39.47 ⫾ 1.21 39.56 ⫾ 1.20
Outcomes at a minimum of 18 months were determined Missing data 0 5
by using a standardized neurologic assessment16 and Birth weight, g
Griffiths’ Mental Developmental Scales,18 from which a Median 3036 3370
development quotient (DQ) was calculated. CP was de- Mean ⫾ SD 3098 ⫾ 615 3395 ⫾ 484
Missing data 0 2
fined according to published criteria.19 Although we had
Apgar score at 1 min
longer-term information for many children, outcomes at Median 8 9
18 to 24 months were analyzed for uniformity. Head Minimum 3 5
growth, occurrence of seizures, and specific visual or Maximum 10 10
speech/language difficulties at any age (range: 2–10 Apgar score at 5 min
years) were noted. For children who could not be eval- Median 10 10
uated by us, specific information was obtained from local Minimum 5 8
pediatric and child developmental services. Outcomes Maximum 10 10
were classified as follows: normal, DQ of ⬎85, normal Resuscitation at birth, n (%)
neurologic examination results and head growth, and None 20 (57) 172 (76)
Minor 13 (37) 55 (24)
absence of seizures; mild, DQ of ⬎85 but with mild
Major 2 (6) 2 (1)
motor impairment (including mild hemiplegia with in- Cord pH
dependent finger movements), suboptimal head growth, ⱕ7.0, n (%) 0 (0) 0 (0)
specific visual or language problems, or seizures or DQ of 7.0–7.1, n (%) 4 (11) 0 (0)
⬍85 but ⬎70 without other complications; moderate, ⱖ7.2, n (%) 8 (23) 183 (80)
DQ of ⬍70, severe hemiplegia, or mild quadriplegia, Not tested, n (%) 23 (66) 46 (20)
with or without seizures; severe, unassessable with the Mean ⫾ SD 7.21 ⫾ 0.10 7.33 ⫾ 0.06
Griffiths’ scales, suboptimal head growth, severe spastic Median 7.26 7.34
quadriplegia, or ongoing seizures. Minimum 7.02 7.20
Maximum 7.35 7.63
Statistical Analyses
Data were analyzed by using StatsDirect 2.5.6 (Stats-
Direct Ltd, Altrincham, Cheshire, United Kingdom).
3098 g; control subjects: mean: 3395 g; P ⫽ .008). There
Where appropriate, unpaired Student’s t tests or Mann-
were more boys among the infants with hypoglycemia
Whitney U tests for continuous data and ␹2 tests or
(P ⫽ .0019).
Fisher’s exact tests for categorical variables were used.
Data were assessed for normality by using the Sharipo-
Wilk test, and the level of significance was set at P ⬍ .05. Prenatal Factors
Infants with hypoglycemia were more likely to be born
to mothers who developed pregnancy-induced hyper-
RESULTS
tension (P ⫽ .04) or had a family history of seizures or
Study Group neurologic disease (P ⫽ .0008). Six of the case subjects
Eighty-four infants with ⱖ1 documented episode of had a family history of seizures. In 1 case, these occurred
early postnatal hypoglycemia and early MRI were iden- in the neonatal period in a second-degree relative, al-
tified. Thirty-nine infants were excluded because of ev- though the cause was unknown. In 5 cases, seizures
idence of HIE and 10 because their MRI was performed began outside the neonatal period, in first-degree rela-
at ⬎6 postnatal weeks, leaving 35 infants who fulfilled tives in 2 cases and in second-degree relatives in 3 cases.
all study criteria.
Perinatal Factors
Overall Case and Control Infant Characteristics There was a significantly lower rate of spontaneous vag-
The case and control infants were comparable with re- inal delivery among case infants (P ⫽ .01), and more
spect to GA (case subjects: mean: 39.47 weeks; range: case infants were delivered through emergency cesarean
37– 42 weeks; control subjects: mean: 39.56 weeks; section (P ⬍ .0001) (Table 1). Case infants were more
range: 37– 42 weeks; P ⫽ .92), birth HC (case subjects: likely to require minor or major resuscitation at birth
mean: 34.28 cm; range: 31– 47.6 cm; control subjects: (P ⫽ .04).
mean: 34.55 cm; range: 31–38; P ⫽ .34), and multiple
births. More case infants demonstrated growth restric- Hypoglycemia Characteristics
tion, defined as birth weight of ⬍10th percentile (case The majority (n ⫽ 30; 86%) had severe hypoglycemia
subjects: n ⫽ 14, 39%; control subjects: n ⫽ 17, 7%; P ⫽ (⬍1.5 mmol/L) on ⱖ1 occasion (Table 2). Twenty-two
⬍.0001), and lower birth weight (case subjects: mean: infants had transient hypoglycemia that resolved promptly

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 TABLE 2 Hypoglycemia Characteristics for the 35 Case Infants TABLE 3 Lesions Detected in 35 Infants With Neonatal
Hypoglycemia Features n (%) Hypoglycemia
Lowest recorded blood glucose level Lesion Site No. With Isolated
ⱕ1.5 mmol/L 30 (86) Hypoglycemia (%)
⬎1.5 mmol/L 5 (14) WM abnormalities 33 (94)
Duration of hypoglycemia Mild 5 (14)
Transient, resolved promptly with treatment 22 (63) Moderate 13 (37)
Prolonged or recurrent 13 (37) Severe 15 (43)
Presentation Nature of severe WM lesions
Symptomatic without seizures 5 (14) Focal hemorrhage 2 (13)
Symptomatic with seizures 22 (61) Unilateral focal MCA infarction 3 (20)
Seizures alone 8 (22) Widespread infarction 10 (67)
Onset of hypoglycemia Global 2 (13)
Day 1 20 (57) Symmetrical posterior parasagittal 6 (39)
Early (within 4 h) 5 (14) Asymmetrical posterior parasagittal 2 (13)
Late (after 4 h) 6 (17) Location of all WM lesions
Unknown 9 (26) Global 13 (39)
Day 2 8 (23) Posterior more than anterior 4 (12)
Day 3 4 (11) Anterior more than posterior 2 (6)
Day 4 3 (9) Posterior only 6 (18)
Associated with growth abnormality Anterior only 0 (0)
IUGR 14 (40) Unilateral 2 (6)
Symmetrical 5 (14) Periventricular 12 (36)
Asymmetrical 9 (26) Posterior 4 (12)
Macrosomia 1 (3) Basal ganglia or thalami lesion 14 (40)
Associated with polycythemia 3 (9) Normal (score 0) 21 (60)
Associated with maternal diabetes mellitus 2 (6) Mild (score 0) 10 (29)
Associated with metabolic/endocrine abnormality Moderate/severe (score 1) 4 (11)
Nonketotic hyperinsulinemic hypoglycemia 1 (3) PLIC
Hypocortisolemia 1 (3) Abnormal/absent myelination 4 (11)
Ketotic hypoglycemia 1 (3) Normal myelination 31 (89)
Glucose-6-phosphate dehydrogenase deficiency 1 (3) Cerebellum 2 (6)
IUGR indicates intrauterine growth restriction. Abnormal SI 1 (3)
Hemorrhage 1 (3)
Cortex 18 (51)
Highlightinga 12 (34)
with glucose administration. Eight of those infants had
Loss of markingsa 9 (26)
intrauterine growth restriction, and 1 had hypocortisol- Brainstem 2 (6)
emia. Thirteen infants had prolonged/recurrent hypogly- Abnormal SI 1 (3)
cemia. Six had intrauterine growth restriction, and 3 had Hemorrhage 1 (3)
an underlying metabolic or endocrine diagnosis (1 each of Extracerebral hemorrhage 5 (14)
glucose-6-phosphate dehydrogenase deficiency, ketotic Intraventricular hemorrhage 3 (9)
hypoglycemia, and nonketotic hyperinsulinemic hypogly- Subarachnoid hemorrhage 0 (0)
cemia). Twenty of the 35 infants presented on day 1. a Not mutually exclusive.
Twenty-two infants experienced symptoms including
seizures, 8 had seizures alone, and 5 did not develop
seizures. Ten infants were detected after routine screen-
ing in the neonatal unit, whereas the remainder were sified as either moderate (n ⫽ 13) or severe (n ⫽ 15). Six
identified only after exhibiting symptoms. infants with moderate and 1 with severe WM injury also
had focal small punctate lesions (Fig 1) consistent with
MRI hemorrhagic injury. Two infants with severe WM
MRI scans were acquired at a median age of 9 days changes had larger areas of focal hemorrhage, 3 had
(range: 1– 42 days). unilateral middle cerebral artery (MCA) territory infarc-
tions (Fig 2), and 10 had more-diffuse WM infarction,
Patterns of Injury most with a predominantly posterior parasagittal distri-
bution (Fig 3).
Normal Findings Among all groups with WM injury, 13 infants (39%)
Two case subjects with transient hypoglycemia (lowest had global involvement (Fig 4), 4 with the most severe
glucose levels: 1.3 mmol/L and 1.2 mmol/L) on day 1 changes in the posterior WM. Six infants (18%) had
had normal MRI findings (Table 3). posterior changes alone (Fig 3), and 12 (36%) had injury
confined to the periventricular regions. Only 2 infants
WM (6%) had solely unilateral lesions, with the remainder
Almost all infants (n ⫽ 33; 94%) had some evidence of having bilateral lesions (1 infant with MCA infarction
WM abnormalities, with the majority (80%) being clas- had additional contralateral changes) (Fig 2). Of the

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FIGURE 1
Hemorrhagic WM abnormality (T1-weighted MRI scan in the sagittal plane, obtained 5
days after birth; GA: 40.57 weeks). There are foci of abnormal SI in the cortex and subcor-
tical WM consistent with hemorrhage (arrow). This pattern of injury often complicates
sagittal sinus thrombosis, which was not detected in this child, although a venogram was
not obtained. There is, however, some abnormally high SI along the tentorium and FIGURE 2
superiorly, consistent with subdural hemorrhage. This child had a normal outcome. Asymmetrical WM and central gray matter abnormality (T2-weighted MRI scan in the
transverse plane, obtained 6 days after birth; GA: 41.29 weeks). There is loss of gray
matter/WM differentiation in the right hemisphere consistent with infarction (short ar-
infants with bilateral injury, 15 had symmetrical row) in the middle and posterior territories of the MCA and associated abnormally low SI
changes. in the lentiform nuclei and head of the caudate nucleus and thalamus (long arrow). There
is additional high SI within the WM on the right frontally (arrowhead), as well as anteriorly
and posteriorly on the left (arrowhead). There is mild ventricular dilation. This child de-
BGT and PLIC veloped left hemiplegia, relative microcephaly, and epilepsy.
Fourteen infants (40%) had some involvement of the
BGT. Four cases were moderate or severe and associated
with abnormal PLIC findings. One of those 4 patients and 1 had abnormal signal intensity in the cerebellum.
had extensive unilateral MCA territory infarction (Fig Five infants had extracerebral hemorrhage, and 3 had
2), 1 had multiple hemorrhagic lesions throughout the germinal layer-intraventricular hemorrhage.
BGT, 1 had complete unilateral loss of myelin associated
with abnormal SI in the lentiform nuclei on the same Patterns of Brain Injury According to Severity of
side and multiple areas of hemorrhage in the WM, and 1 Hypoglycemia
had only mildly abnormal SI within the PLIC associated The median value of the lowest recorded blood glucose
with posterior parasagittal infarction. The 10 milder BGT reading was 1.0 mmol/L (range: 0 –2.5 mmol/L). Thirty
lesions predominantly involved abnormal SI in either infants had severe hypoglycemia (ⱕ1.5 mmol/L), and 5
the thalamus or lentiform nuclei; 3 infants had changes had mild hypoglycemia (⬍2.6 to ⬎1.5 mmol/L). The
in the globus pallidi (Fig 5), and all had a normal- severity of hypoglycemia was not associated with spe-
appearing PLIC. The 2 other infants with focal arterial cific patterns of injury.
infarction had no involvement of the PLIC.
Patterns of Brain Injury According to Duration of
Cortex Hypoglycemia
Eighteen (51%) infants had cortical abnormality. In Twenty-two infants responded rapidly to treatment,
34% this was cortical highlighting and in the majority of without subsequent recurrence. In 13 infants, the hypo-
cases, this was widespread and in a parasagittal distribu- glycemia was either prolonged or recurrent. No striking
tion. Twenty-six percent of infants had loss of cortical distinguishing MRI features were seen for infants with
markings, a finding associated with early cortical infarc- transient versus prolonged/recurrent hypoglycemia.
tion and often seen adjacent to WM injury, giving rise to
a loss of gray matter/WM differentiation. A small num- Patterns of Brain Injury According to the Presence of Seizures
ber of infants (n ⫽ 3) had both abnormalities. Nine children had seizures over a period of several days;
all had moderate or severe WM injury and 7 had cortical
Other Sites involvement. Five children did not develop seizures; 1
Injury in other sites was rare. One infant had abnormal had normal MRI findings, 1 had mildly abnormal WM, 3
SI in the brainstem, 1 had a small hemorrhagic lesion had moderately abnormal WM, and none had cortical

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FIGURE 3
Posterior WM abnormality (T2-weighted MRI scan in the transverse plane obtained 14
days after birth; GA: 39.71 weeks). There is severely abnormally high SI with loss of gray
FIGURE 4
matter/WM differentiation bilaterally in the posterior parietal and occipital lobes (ar-
Abnormal WM and normal BGT (T1-weighted MRI scan in the transverse plane, obtained
rows). Appearances within the BGT and PLIC are normal. This child developed cognitive
9 days after birth; GA: 39 weeks). There is generalized low SI throughout the WM (long
delay, epilepsy, and impaired vision.
arrows) and smaller foci of low SI within the subcortical WM (short arrow), most obvious
posteriorly. Appearances within the BGT are normal. This child exhibited normal findings
at the follow-up evaluation.
involvement. For the remaining 21 children who had
transient seizures on day 1, the MRI findings ranged
from normal findings to a severe pattern of injury.
Two children thought to have normal cognitive abilities
had some speech and language delays.
Neurodevelopmental Outcomes
Overall Findings Seizures
Information was available for 34 of 35 children at a Twelve children developed later seizures. Three had in-
minimal age of 18 months. Eight children had normal fantile spasms, 2 had generalized seizures, 1 had focal
outcomes, 15 had mild impairments, 8 had moderate seizures, and 1 had seizures associated with later recur-
impairments, and 3 had severe impairments. The child rent hypoglycemia. The seizure types were not specified
for whom no outcome data were available had normal for 2 infants, and 3 infants had febrile seizures. All
scan results and early transient hypoglycemia. seizures developed before the age of 2 years.

Motor Abilities Head Growth

Twenty-five children demonstrated normal findings, 6 Nine of 28 children with HC measurements at 2 years
had CP (3 spastic quadriplegia and 3 hemiplegia), and 3 had suboptimal head growth (decrease of ⬎2 SD across
had mild motor delays. Twenty-nine children (85%) the percentiles, compared with HC at birth).
were walking by 2 years of age. Four children were not
yet 2 years of age when outcome data were obtained; Vision
however, all except 1 were already walking by the time The following abnormalities were noted: squint (n ⫽ 5),
of assessment. The exception was a child who had de- field defect (n ⫽ 2), cortical visual impairment (n ⫽ 2),
veloped severe spastic quadriplegia. immature visual attention and tracking (n ⫽ 1), and
visuospatial difficulties (n ⫽ 1).
Cognition
Nineteen children were functioning in the reference Relationship Between Hypoglycemia and Outcomes
range, 3 had mild delays, 5 had moderate delays, and 5 All except 1 of the infants with early transient hypogly-
could not be assessed with standard testing methods. cemia and all 5 infants who did not have seizures had

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 TABLE 4 Severity of Outcomes and Patterns of Injury on MRI Scans
No. (%)
Normal Mild Moderate Severe
(n ⫽ 8) (n ⫽ 15) (n ⫽ 8) (n ⫽ 3)
WM
Normal 1 0 0 0
Mild 1 4 0 0
Moderate 4 7 2 0
Severe 2 4 6 3
Nature of severe WM lesions
Focal hemorrhage 0 0 1 1
Focal infarction 1 1 1 0
Widespread infarction 1 3 4 2
Global 1 0 0 1
Symmetrical posterior parasagittal 0 1 4 1
Asymmetrical posterior parasagittal 0 2 0 0
Location of all WM lesions
Global 4 5 4 2
Posterior more than anterior 0 1 2 1
Anterior more than posterior 1 0 0 1
Unilateral 1 1 0 0
Posterior only 0 2 3 1
Anterior only 0 0 0 0
Periventricular 3 8 1 0
Posterior 2 2 0 0
BGT involvement
FIGURE 5 Normal 6 9 3 2
BGT abnormality (T1-weighted MRI scan in the transverse plane, obtained 3 days after Mild 2 4 3 1
birth; GA: 40 weeks). There is bilaterally increased SI in the region of the globus pallidum Moderate/severe 0 2 2 0
(arrow). In addition, there is some low SI in the lentiform nuclei on the left and there are PLIC
some small areas of cortical highlighting in the depths of the central sulci (not shown). Abnormal or absent myelination 0 2 2 0
This child exhibited normal cognitive and motor development at the follow-up evalua- Normal myelination 8 13 6 3
tion but had developed a squint.
Cortex
Normal 4 7 3 2
Cortical highlightinga 3 4 4 1
Loss of markingsa 2 5 2 0
outcomes within the reference range or mildly abnormal a Not mutually exclusive.
outcomes. The infant from this group with a moderately
abnormal outcome had an extensive MCA infarction,
with severe hemiplegia, infantile spasms, a visual field DISCUSSION
defect, and delayed speech and language development. This is the first study of a large cohort of term symptom-
Outcomes were more varied for infants with prolonged atic infants with hypoglycemia that assesses MRI injury
or severe hypoglycemia. patterns in relation to clinical presentations and neuro-
developmental outcomes. We show that the patterns of
brain injury detected on early MRI scans are more varied
MRI Findings and Outcomes than those described in the literature. Previous smaller
Outcomes correlated well with MRI findings (Table 4). studies with heterogeneous cohorts reported that the
Infants with CP either had a unilateral focal infarction or most severe injury is localized to the parietal and occip-
posterior parasagittal infarction involving the PLIC, giv- ital cortex and subcortical WM.9–15,20 In our study, which
ing them hemiplegia (n ⫽ 2), or had severe bilateral WM was confined to term infants and excluded infants with
injury, giving them spastic quadriplegia (n ⫽ 3); 1 infant HIE, only 29% of subjects showed a primarily posterior
with hemiplegia had bilateral WM injury with asymmet- pattern of injury.
rical involvement of the thalami. The other 2 infants Why the parietal and occipital lobes should be most
who had PLIC changes had delayed fine motor skills at severely affected after neonatal hypoglycemia is unclear.
the follow-up evaluations. Nine of the 14 children who There are several putative mechanisms for hypoglyce-
had severe global WM changes had very low DQ values mia-induced cellular injury, including excitatory neuro-
or could not be assessed; the other 5 children had nor- toxins active at N-methyl-D-aspartate receptors,21,22
mal or mildly abnormal outcomes, but all had either increased mitochondrial free radical generation and ini-
unilateral or asymmetrical WM injury with a normal tiation of apoptosis,23 and altered cerebral energetic
BGT. Eight children had WM infarction (2 asymmetrical characteristics.24 The parietal/occipital lobes are not
and 6 symmetrical) in the posterior parasagittal region; known to be particularly vulnerable to these effects, but
asymmetrical injury was associated with milder out- some occipital regional vulnerability has been demon-
comes than symmetrical injury. strated as increased regional cerebral blood flow during

PEDIATRICS Volume 122, Number 1, July 2008 71

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hypoglycemia, with significant reduction in regional glu- have acute neurologic dysfunction. Six other subjects
cose uptake in the occipital WM.25 This might make this (17%) had risk factors associated with either poor feed-
region more vulnerable, although our data suggest that ing, hyperinsulinism, or suboptimal hormone/enzyme
the posterior WM and cortex may not be as selectively responses to hypoglycemia, but 15 subjects (43%) had
vulnerable as suggested previously. no known risk factors. We did not find other prenatal,
WM injury was the most common abnormality intrapartum, or postpartum factors that could account
among the group, and 80% of cases were classified as for the patterns of injury or neurologic symptoms seen
moderate or severe. The vulnerability of WM to hypo- among the case subjects. Although there were higher
glycemia-induced injury raises the possibility of an ex- rates of delivery through emergency cesarean section
aggerated pathophysiological response, compared with and a tendency to need more resuscitation among the
other cerebral tissue types. Abnormal cerebral blood case subjects (although none required cardiac compres-
flow occurs in preterm human neonates and in animal sions or drugs), the cord pH values, Apgar scores at 1 and
models of neonatal hypoglycemia,26–28 which might ac- 5 minutes, and clinical assessment findings were not
count for the periventricular distribution of injury seen consistent with HIE. It is possible that adverse peripar-
in some of our infants. Given the maturation-dependent tum events rendered the case infants more susceptible to
vulnerability of the WM of preterm infants to various brain injury in the context of hypoglycemia, but there
injurious processes,29 it is possible that infants who are was no evidence that other causal factors accounted for
vulnerable to the adverse cerebral effects of hypoglyce- the patterns of injury or the neurologic dysfunction ob-
mia have less-mature WM, although we did not see served.
evidence of this in conventional analyses. A limitation of our study was that we did not have
Approximately 30% of our cohort had WM lesions detailed early feeding histories or knowledge of maternal
consistent with hemorrhage; 20% were focal, and 80% medication use, which might have enabled us to identify
were multiple and punctate, mainly in the periventricu- other case infants who were at risk of metabolic malad-
lar WM. It is unclear whether these lesions definitely aptation. Transient hyperinsulinism has been reported
represent hemorrhage, because we have no postmortem for 3 of 4 infants who had symptomatic hypoglycemia
histologic data; it is possible that they are ischemic or and abnormal MRI findings.33 The suppressed produc-
ischemic with secondary hemorrhage, and they may be tion of alternative cerebral fuels that accompanies hy-
of arterial or venous origin. Hemorrhage has not been perinsulinism could render infants with this abnormality
reported previously in association with hypoglycemia. more susceptible to injury, and the profiles of hormones
Hypoglycemia and polycythemia may cooccur, and this and enzymes involved in early glucose regulation in this
raises the possibility of cerebral venous thrombosis, al- group of infants warrant further investigation.
though no definite evidence for this was seen on the There was no relationship between the severity or
MRI scans. However, the mean postnatal age at the time duration of hypoglycemia and neurodevelopmental out-
of MRI was 9 days, which is late for reliable detection of comes. The data that suggested such associations were
venous thrombosis, and optimal MRI sequences were from specific groups, such as preterm infants34 and hy-
not used for all infants. Focal arterial territory infarction poglycemic infants of mothers with diabetes mellitus,35
occurred in 3 infants. An association between this form and from severe, protracted, insulin-induced hypoglyce-
of stroke, which may have a thrombotic or embolic mia in monkeys.36 Our study was not designed to test
pathogenesis, and hypoglycemia was reported by Bend- this relationship; to do so would require larger numbers
ers et al30 for preterm infants, although no clear expla- and more-precise measures of the duration of hypogly-
nation was elucidated. cemia.
Severity of WM injury was a good predictor of out- A significant number of infants had adverse sequelae.
comes at a minimal age of 18 months; 80% of infants Cognitive impairment was more likely than motor impair-
with moderate or severe outcomes had severe WM in- ment to be severe, because most children were walking by
jury, whereas no infant with mild WM injury had more 2 years of age; this correlates with the predominant pattern
than a mildly abnormal outcome. Infants who had se- of WM injury, with sparing of the BGT and PLIC. One of
vere WM changes with normal/mildly abnormal out- the 3 infants with an MCA infarction developed hemiplegic
comes all had either unilateral or asymmetrical injuries, CP, which could be predicted from the site of the infarc-
which suggests that the relatively preserved hemisphere tion,37 whereas those who developed spastic quadriplegia
was able to compensate functionally for the severely all had severe bilateral WM changes. The mild, PLIC-spar-
damaged side. ing BGT lesions we found were different from those seen in
Although glucose is the primary fuel for cerebral ox- HIE and did not seem to affect early motor outcomes
idative metabolism, the normal metabolic adaptation to adversely; however, longer follow-up monitoring is
postnatal life involves the use of lactate31,32 and ketone needed to confirm both this finding and the prevalence of
bodies2 as alternative substrates for oxidative metabo- subtle cognitive deficits. Although we did not present the
lism. Fourteen (40%) of the case subjects had growth data, cognitive impairments and seizures have persisted for
restriction and thus were at risk because of reduced children for whom we have later outcome data. Head
substrate stores and less ability to generate and/or to use growth was suboptimal by ⬎2 SD for one third of infants,
alternative fuel sources in the event of hypoglycemia. and only 25% had HC values of ⬎50th percentile in fol-
However, the MRI findings were not typical of those low-up evaluations, consistent with the high rates of WM
seen among infants with growth restriction who do not injury.38

72 BURNS et al
Downloaded from pediatrics.aappublications.org at Galter Health Sciences Library on September 4, 2014
 Visual impairments and epilepsy were common, and 8. Larroche JC. Developmental Pathology of the Neonate. New York,
both are reported outcomes associated with neonatal NY: Excerpta Medica; 1977
hypoglycemia.20,39 Thirty-one percent of our cohort had 9. Barkovich AJ, Ali FA, Rowley HA, Bass N. Imaging patterns of
visual abnormalities at 2 years and this might have been neonatal hypoglycemia. AJNR Am J Neuroradiol. 1998;19(3):
523–528
underestimated, because formal detailed visual assess-
10. Aslan Y, Dinc H. MR findings of neonatal hypoglycemia. AJNR
ment was not performed for all children. The majority of Am J Neuroradiol. 1997;18(5):994 –996
our infants with abnormal vision did have involvement 11. Kinnala A, Korvenranta H, Parkkola R. Newer techniques to
of the posterior cortex and WM; however, some with study neonatal hypoglycemia. Semin Perinatol. 2000;24(2):
severe occipital injury had apparently normal visual de- 116 –119
velopment. Twenty-seven percent of our infants devel- 12. Murakami Y, Yamashita Y, Matsuishi T, Utsunomiya H,
oped later seizures. Infants with symptomatic hypogly- Okudera T, Hashimoto T. Cranial MRI of neurologically im-
cemia were more likely to have a family history of paired children suffering from neonatal hypoglycaemia. Pediatr
seizures. In one case these were neonatal seizures of Radiol. 1999;29(1):23–27
unknown aetiology in a second degree relative, and in 13. Spar JA, Lewine JD, Orrison WW Jr. Neonatal hypoglycemia: CT
and MR findings. AJNR Am J Neuroradiol. 1994;15(8):1477–1478
the remaining 5 cases the onset of seizures was in child-
14. Alkalay AL, Flores-Sarnat L, Sarnat HB, Moser FG, Simmons CF.
hood or adulthood in a first degree relative (2 cases) or Brain imaging findings in neonatal hypoglycemia: case report and
second degree relative (3 cases). review of 23 cases. Clin Pediatr (Phila). 2005;44(9):783–790
15. Cakmakci H, Usal C, Karabay N, Kovanlikaya A. Transient
neonatal hypoglycemia: cranial US and MRI findings. Eur Ra-
CONCLUSIONS
diol. 2001;11(12):2585–2588
The patterns of injury associated with symptomatic neona- 16. Haataja L, Mercuri E, Regev R, et al. Optimality score for the
tal hypoglycemia are more diverse than reported previ- neurologic examination of the infant at 12 and 18 months of
ously. Valuable information regarding the neurodevelop- age. J Pediatr. 1999;135(2):153–161
mental outcomes of infants with hypoglycemia can be 17. Mercuri E, Dubowitz L, Brown SP, Cowan F. Incidence of
ascertained from brain MRI in the neonatal period, and cranial ultrasound abnormalities in apparently well neonates
MRI findings are more instructive than the severity or on a postnatal ward: correlation with antenatal and perinatal
duration of hypoglycemia as prognostic indicators of later factors and neurological status. Arch Dis Child Fetal Neonatal Ed.
outcomes. Poor cognition and seizures were relatively 1998;79(3):F185–F189
common in our patients at 2 years, and there is clearly a 18. Griffiths R. The Abilities of Young Children: A Comprehensive Sys-
tem of Mental Measurement for the First Eight Years of Life. London,
need for longer-term follow-up monitoring to assess the
England: Child Development Research Centre; 1970
functional impact of these problems at school age. 19. Bax M, Goldstein M, Rosenbaum P, et al. Proposed definition
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ACKNOWLEDGMENTS
20. Caraballo RH, Sakr D, Mozzi M, et al. Symptomatic occipital
This work was supported by Philips Medical Systems (Best, lobe epilepsy following neonatal hypoglycemia. Pediatr Neurol.
Netherlands), the Medical Research Council, the Academy 2004;31(1):24 –29
of Medical Sciences, and the Health Foundation. 21. Papagapiou MP, Auer RN. Regional neuroprotective effects of the
We are grateful to the nursing, medical, and radio- NMDA receptor antagonist MK-801 (dizocilpine) in hypoglyce-
graphic staff members who were involved in scanning, mic brain damage. J Cereb Blood Flow Metab. 1990;10(2):270 –276
the parents who consented to take part, and the consul- 22. Wieloch T. Hypoglycemia-induced neuronal damage pre-
tant colleagues who referred infants. vented by an N-methyl-D-aspartate antagonist. Science. 1985;
230(4726):681– 683
23. Ballesteros JR, Mishra OP, McGowan JE. Alterations in cere-
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GENETICS MAY AFFECT ATHLETE DOPING TESTS

“A genetic quirk could help cheating athletes beat drug tests and could
unfairly taint fair players. The genetic variation affects an enzyme that
processes testosterone. Testosterone is naturally made in the body by both
men and women, although it is primarily known as a male sex hormone. In
order to distinguish between naturally present hormone and synthetic tes-
tosterone from steroid use, drug tests measure a ratio of two chemicals found
in urine. One chemical, epitestosterone glucuronide (EG), is made at a
constant level in the body, regardless of testosterone levels. The other chem-
ical, testosterone glucuronide (TG), is a testosterone by-product. Testers
measure the ratio of TG to EG. Any amount of TG greater than four times the
level of EG is considered a red flag for doping. About 15% of 145 healthy
male volunteers lacked the enzyme entirely. Just over half the volunteers
(52%) had one copy of the gene, and one-third of the men had two copies.
Some of the men were selected to get a single shot of testosterone. The
researchers monitored production of TG in the men’s urine for 15 days after
the injection. About 40 percent of the people who lacked the enzyme never
secreted enough TG to raise warning flags in the standard test, even after
getting a hormone shot, the team reports online in the Journal of Clinical
Endocrinology & Metabolism. ‘There is a risk that many such individuals have
escaped detection,’ says Anders Rane of the Karolinska Institute in Stock-
holm, Sweden, and one of the authors of the study.”
Saey TH. Science News. Vol.173; 195. March 29, 2008
Noted by JFL, MD

74 BURNS et al
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 Patterns of Cerebral Injury and Neurodevelopmental Outcomes After
Symptomatic Neonatal Hypoglycemia
Charlotte M. Burns, Mary A. Rutherford, James P. Boardman and Frances M. Cowan
Pediatrics 2008;122;65
DOI: 10.1542/peds.2007-2822
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