Neurologic aspects of neonatal hypoglycemia

Abstract

Profound neonatal hypoglycemia is one of the leading causes of brain injury. Hypoglycemic encephalopathy is caused by lack of glucose availability to brain cells. Although sharing a similar pathogenesis with hypoxic-ischemic encephalopathy, hypoglycemic brain insult has distinctive metabolic, brain imaging, electroencephalographic and histopathologic findings.

Full text

Neurologic Aspects of Neonatal Hypoglycemia
Arie L. Alkalay
MD
1
, Harvey B. Sarnat
MD
2*
, Laura Flores-Sarnat
MD
2*
and Charles F. Simmons
MD
1
Divisions of
1
Neonatology and
2
Neurology, Department of Pediatrics, Ahmanson Pediatric Center, Cedars-Sinai Medical Center,
Los Angeles, CA, USA
Affiliated to David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
Key words:
neonatal hypoglycemia, hypoglycemic encephalopathy
Abstract
Profound neonatal hypoglycemia is one of the leading causes of brain
injury. Hypoglycemic encephalopathy is caused by lack of glucose
availability to brain cells. Although sharing a similar pathogenesis with
hypoxic-ischemic encephalopathy, hypoglycemic brain insult has
distinctive metabolic, brain imaging, electroencephalographic and
histopathologic findings.
IMAJ 2005;7:188±192
Neonatal hypoglycemia is a common condition. While most infants
do not have neurologic sequelae, a few develop severe neurologic
damage. Neonatal hypoglycemia is one of the leading causes of
brain injury. The incidence of neonatal hypoglycemia depends on
the definition of low blood glucose threshold. If the low blood
glucose threshold in the first 2 days in term infants is defined as
whole blood glucose
4
40 mg/dl (the currently acceptable defini-
tion), or
4
30 mg/dl (historical definition), the incidence will be
8.1% and 20.6%, respectively [1]. Many conditions are associated
with neonatal hypoglycemia; these include common conditions
[Table 1] as well as relatively rare conditions such as hormonal
disorders, inborn errors of metabolism, glucose transporter
deficiencies, and insulin-producing tumors. In this article we review
the neurologic aspects of neonatal hypoglycemia; the pathophy-
siology, prevention and treatment of neonatal hypoglycemia are
beyond the scope of this review.
Neurologic overview
In theory, neuropathologic lesions of hypoglycemic encephalopathy
should be very similar to those of hypoxic-ischemic encephalopathy
because the essential substrates of oxidative phosphorylation,
glucose and oxygen, respectively, are the limiting factors. As
neurons have small reserves of glycogen but not oxygen, one might
expect that lesions due to hypoglycemia would be somewhat slower
in evolution and less severe. Nevertheless, prolonged, severe
hypoglycemia in humans may induce extensive neuronal necrosis
[2]. An important difference between HGE and HIE is that HIE is
associated with severe lactic acidosis whereas HGE is not; lactic
acidosis contributes significantly to neuronal degeneration. This
capacity disappears with the progressive inability of lactate to enter
the brain with maturation [3]. Neonatal resistance to hypoglycemic
brain injury may be due to a combination of enhanced cerebral
blood flow enabling cerebral uptake of glucose, enhanced ability to
use alternative substrates (especially ketone bodies), lactate, and
preservation of cerebral high energy phosphates [4]. Ketonemia is
protective to the neonatal brain, which is subjected to hypoglyce-
mia and hypoxia-ischemia, because of the substrate's ability to
undergo oxidative decarboxylation and thus provide reducing
Reviews
* Dr. Harvey Sarnat and Dr. Laura Flores-Sarnat are currently at the Alberta
Children's Hospital, Calgary, Canada
HGE = hypoglycemic encephalopathy
HIE = hypoxic-ischemic encephalopathy
Table 1.
Common conditions associated with neonatal hypoglycemia*
Cause/
associated
condition
Inadequate
production
of glucose**
Excessive
utilization
of glucose*** Comments
Prematurity + ? Mainly due to depletion of
glycogen stores
IUGR infants + + Hyperinsulinism in many
infants, decreased
gluconeogenesis, and rapid
growth
IDM infants + Hyperinsulinism
Perinatal stress + + Anaerobic metabolism, and
depletion of glycogen stores
Polycythemic
infants
+ Increased RBC mass causing
excessive utilization
Non-IDM LGA
infants
Cause not well established
Post-term
infants
+ Depletion of glycogen stores
Sepsis + + Decreased gluconeogenesis,
and increased utilization
CHF and CHD + Increased utilization
Erythroblastosis
fetalis
+ Increased insulin levels
High UAL + Increased insulin production
due to excessive glucose
perfusion of the pancreas
Maternal
medications
+ Such as ritodrine, terbutaline
and other medications
* Modified from ref. 1.
** Inadequate production of glucose secondary to lack of glycogen stores,
decreased glycogenolysis and decreased gluconeogenesis.
*** Excessive utilization of glucose secondary to hyperinsulinism and/or an
increased rate of anaerobic glycolysis.
IUGR = intrauterine growth restriction, IDM = Infant of diabetic mother,
LGA = large for gestational age,
CHF = congestive heart failure, CHD = cyanotic heart disease,
UAL = umbilical artery line.
188 A.L. Alkalay et al.
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equivalents to mitochondria for energy production [5]. However,
hyperinsulinemia, a common finding in infants of diabetic mothers,
suppresses the production of ketone bodies and therefore
decreases alternate fuel production. Additional protective mechan-
isms include glycogen stores in astrocytes [6] and a low cerebral
metabolite rate for glucose, which are about 30% lower than in
adults [7].
In rats, hypoglycemic brain damage is minimized by the blocking
of NMDA (N-methyl-D-aspartate) receptors to the acute neurotoxic
effects of the release of large amounts of excitatory neurotransmit-
ters [8]. Therefore, excitatory amino acids may play a role in causing
brain damage. Hypoglycemia may induce neuronal death by
interfering with mitochondrial energy production. Swelling and
proteinaceous flocculent degradation of mitochondria are seen in
hypoglycemic rat brains, in neuronal bodies and also in dendrites
[9]. Apoptosis, which is programmed cell death and a major
mechanism in neuronal loss, is triggered by a variety of stimuli
including hypoglycemia [10]. Fas is a cell surface receptor that on
activation initiates a cascade that leads to apoptosis. Caspases
intracellular cysteine proteases are activated and convey an
apoptotic signal in a proteolytic cascade of caspases, leading to
degradation of cellular targets and apoptosis [11]. It was shown that
the use of insulin-like growth factor-I and bcl-2 (B cell lymphoma-2),
which are anti-apoptotic factors, can prevent or ameliorate
hypoglycemic brain injury [10].
Neuropathologic findings
HIE and HGE have overlapping features but also differ substantially,
in both the experimental animal and the human, where they are
often concurrent conditions. The principal generalization from
human postmortem, human and animal studies is that HIE often
results in cerebral infarcts. In contrast, HGE tends not to cause
extensive necrosis, but rather produces individual neuronal death
throughout the brain with a characteristic vulnerability of certain
neurons and resistance of others [9]. Some of the most vulnerable
neurons to hypoglycemia are resistant to hypoxia, and vice versa.
Even in human adults who died from pure hypoglycemic coma, the
brain may exhibit selective neuronal loss without extensive tissue
infarction [2]. The involvement of the occipital lobes found by
magnetic resonance imaging and computerized tomography studies
has been confirmed also by autopsy findings [12]. Selective swelling
of dendrites is an early neuronal lesion in hypoglycemia. This
feature resembles neurotoxic damage from sudden release of
excitatory amino acids [9].
The human neonatal lesions traditionally described in textbooks
of neuropathology include pyknosis and karyorrhexis of neuronal
nuclei and neuronal loss in the cerebral cortex, Ammon's horn and
the dentate gyrus of the hippocampus, basal ganglia and thalamus,
particularly after multiple episodes of hypoglycemia. The cerebral
cortex, brainstem and cerebellum appear to be more resistant to
hypoglycemia [9,13,14]. While the dentate gyrus of the hippocam-
pus is vulnerable to hypoglycemia, it is relatively resistant to
hypoxia [2]. Laminar necrosis involving layers 2 and 3 of the
cerebral cortex in human infants [15] and similar lesions in insulin-
induced hypoglycemia in monkeys [16], with relative sparing of the
cerebellar cortex and brainstem, were described in early neuro-
pathologic studies. Brainstem neurons are remarkably resistant to
irreversible injury by hypoglycemia. In global ischemia, by contrast,
watershed zone infarcts often occur in the tegmentum of the
midbrain, pons and medulla [17]. Selective degeneration of the
pontine nuclei as pontosubicular degeneration is a characteristic
and common lesion in premature infants who have suffered HIE but
does not result from neonatal HE [14]. Neonatal rats rendered
hypoglycemic for 18 days postnatally exhibited reduced brain
weight, decreased myelin lipids and proteins, and cellular loss
throughout the brain [18]. Mitochondrial swelling and degradation
were shown to occur in neurons, including dendrites [9].
The predilection for the occipital lobes in HGE may be related
to intensive axonal extension and synaptogenesis, which occur in
the occipital lobes during the neonatal period, and are sensitive to
glucose availability [19]. Of note, layer 4 of the primary visual cortex
is larger, with more neurons and synapses than any other region in
the cerebral cortex, and is therefore more susceptible to laminar
necrosis [20]. A comparison of the neuropathologic lesions of
hypoxia-ischemia and hypoglycemia is summarized in Table 2.
Based on published data [21,22], it is safe to conclude that
human neonates who sustain profound hypoglycemia for hours may
be at significant risk for an adverse neurologic outcome. Two
studies delineated specifically the duration and the glucose levels
that may cause brain insult. Seven newborns developed seizures
when their plasma glucose levels were in the range of 2±11 mg/dl
for a period of 12 hours or longer [21]. Two near-term infants had
permanent abnormal brain imaging studies, after having PGLs as
low as 2 and 4 mg/dl, and had a total length of hypoglycemia of 4
and 10 hours respectively [22]. According to one study [23],
recurrent episodes of hypoglycemia are a more predictable risk
factor for long-term sequelae than a single episode. A population
meta-analysis of hypoglycemic infants showed that in more than
Reviews
PGL = plasma glucose level
Table 2.
Comparison between hypoglycemia and hypoxia-ischemia brain insult
Parameter Hypoxia-ischemia Hypoglycemia
Cause Reduced oxygen
availability
Reduced glucose
availability
Serum lactic acid Increased Normal
Cerebral cortex Infarction in watershed
zones
Selective neuronal
necrosis
Cerebral cortex Layers Middle laminae
layers 3, 5, 6 Superficial laminae layers 2,3,4
Hippocampus CA1, CA3 CA1, dentate gyrus
Cerebellum Purkinje neurons Absent
Brainstem Tegmental watershed
zone
Absent
Imaging studies Non-specific Occipital lobe
(occasionally parietal
lobe)
EEG Non-specific
Non-specific, or occipital
lobe epilepsy
CA =
cornu ammonis
(Latin), CA1 CA4 are parts of the hippocampus.
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95% of newborn infants with hypoglycemia-associated severe
neurologic sequelae, plasma glucose concentrations of <25 mg/dl
were first detected at least 10 hours after birth. The incidence of
severe neurologic injury in these infants is 28% with 95% confidence
interval of 18 37% [Submitted].
Symptomatology
The neurologic symptoms of neonatal hypoglycemia are non-
specific. Neurologic symptoms may appear gradually, with irrit-
ability, tremor, jitteriness, eye rolling, seizures, hypotonia, exag-
gerated Moro reflex, and progression to seizures and acute
encephalopathy, lethargy and coma. The most common clinical
finding reported by some authors is an altered level of alertness,
characterized as a combination of jitteriness and stupor [24].
Seizures may start very early after onset of hypoglycemia, but
usually appear after 12 hours of continuous or recurrent significant
hypoglycemia. The presence of seizures correlates with severity of
hypoglycemia. Occasionally, seizures have been described as focal
jerking of the arms and legs, tonic or tonic-clonic. At follow-up,
many of these patients persist with epilepsy of different types,
including infantile spasms and partial seizures [24]. Although there
is no pathognomonic symptomatology for neonatal hypoglycemia,
the clinical findings that are depicted in Table 3 have been
attributed to hypoglycemia, based mainly on resolution of
hypoglycemia symptoms after treatment [25,26].
Jitteriness is not a very useful confirmatory sign for hypoglycemia
since it occurs frequently in newborn infants. In fact it was reported
in as many as 44% of 936 healthy full-term infants [27]. Tremor
(tremor and jitteriness are terms that are often used interchange-
ably) is also a frequent neonatal sign. In the majority of healthy
neonates (84 of 102) the tremor disappeared when consoled by
suckling stimulation. Only those infants in whom the tremor
continued during suckling stimulation had either hypoglycemia or
hypocalcemia [28]. Jitteriness is not always physiologic however,
and may indicate release of monosynaptic spinal cord stretch
reflexes from corticospinal tract inhibition in term neonates, due to
impaired function of the large inhibitory motor pyramid cells of
layer 5 and 6 of the cerebral cortex [29].
Neurologic sequelae
At follow-up, neonatal hypoglycemia may lead to reduced head
circumference, lower than expected psychomotor scores, motor
deficit, and mental retardation [Submitted]. Neonates with
recurrent episodes of hypoglycemia have lower scores in psycho-
motor development at follow-up than neonates with a single
episode [23]. In a prospective controlled study, 39 treated
hypoglycemic infants (PGL <25 mg/dl, mean
+
SD weight 1,633
+
578 g, gestational age 34.8
+
4.7 weeks) and 41 matched
controls were assessed for 5±7 years in terms of physical,
neurologic, intellectual, developmental, and electroencephalo-
graphic findings. A larger number of hypoglycemic infants (
P
<
0.05) had IQ scores of <86 and significantly smaller mean head
circumference as compared to the control infants [30]. In a
multicenter study, in newborn infants (mean
+
SD weight 1,337
+
315 g, gestational age 30.5
+
2.7 weeks) with moderate
hypoglycemia (PGL <45 mg/dl), an abnormal neurodevelopmental
outcome and increased incidence of cerebral palsy was found at the
age of 18 months postnatally, as compared to matched euglycemic
infants [31]. At age 8 years however, the incidence of cerebral palsy
was not different between the two groups (authors' comment). The
relative risk of neurodevelopmental impairment in newborns who
were subjected to hypoglycemia during 5 or more days, compared
with newborns without hypoglycemia, was 3 5:1 [32].
Seizures are usually the first presenting symptom of profound
hypoglycemia (PGL
4
25 mg/dl) [Submitted]. Seizures that are
associated with hypoglycemia have a worse prognosis than
hypoglycemia without seizures [33]. Visual impairment due to
profound neonatal hypoglycemia is associated with injury of the
occipital lobes [Submitted].
Electroencephalogram
Changes in the EEG pattern in hypoglycemic infants reflect changes
in the functional state of synaptic activity and, as with HIE, may
have no distinctive features to be diagnostic. A recent study
described 15 children (mean age 12 years) who developed severe
neurologic sequelae after neonatal hypoglycemia. Thirteen had
brain lesions in the occipito-parietal area, and 11 had occipital lobe
epilepsy [34]. In another study of 20 newborns with symptomatic
hypoglycemia, the EEG showed increased density of frontal sharp
transient waves in all sleep stages when compared with controls.
This increase was even higher in small for gestational age newborns
[35].
Auditory evoked potentials
In five neonates studied with brainstem auditory evoked response
and somatosensory evoked potentials during episodes of hypogly-
cemia, significant abnormalities (prolongation of latencies) were
recorded [36]. Half of these patients were clinically asymptomatic.
The abnormal findings returned to normal after the administration
of glucose. However, a more recent and larger study [37] could not
confirm and reproduce the results of the previous study. In the
future, it remains to be seen if profound hypoglycemia is associated
with hearing impairment.
Neuroimaging
Brain imaging studies in the acute phase demonstrate generalized
edema and bilateral patchy hyperechogenic areas. Follow-up brain
Reviews
Table 3.
Clinical manifestations of neonatal hypoglycemia*
Central nervous system response Autonomic nervous system response
Apnea, tachypnea
Cyanosis**, dusky spells
Eye rolling, seizures
Jitteriness, tremor, irritability
Lethargy
Tachycardia
Poor feeding
Diaphoresis
Other rare autonomic responses such as:
Instability of blood pressure
Episodes of bradycardia
Increased bronchotracheal secretions
Gastrointestinal paralysis
Low temperature
* Modified from ref. 1.
** Cyanosis may be due to apnea, autonomic nervous system stimulation, or
decreased pulmonary blood flow
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CT and MRI scans showed parenchymal hypodensities, predomi-
nantly in the occipital lobes [19]. A review of 23 neonates with
abnormal brain imaging studies due to profound hypoglycemia
showed that the median and range of age at clinical presentation
when hypoglycemia was first detected occurred at 30 hours and
1±72 hours respectively [Submitted]. The median and range of
plasma glucose levels at that time was 14 mg/dl and 1±43 mg/dl
respectively. Of the 23 patients, 6 (26%) showed only transient brain
changes in imaging studies and normal follow-up studies, while 17
(74%) showed persistent brain insult in imaging studies. The cases
with persistent abnormal imaging brain findings had a much higher
likelihood for adverse neurologic outcome, as compared to the
cases with transient findings (
P
< 0.05, Fisher's exact test). The
imaging findings in these infants and their neurologic outcome are
depicted in Table 4.
Advanced imaging technology [38,39], such as diffusion-
weighted imaging and apparent diffusion coefficient mapping (for
detecting early brain injury), diffusion tensor imaging (for detecting
abnormal myelinization in small injuries of white matter), and
magnetic resonance spectroscopy (for detecting lactate, creatine
and other metabolites), may help in the future to delineate
hypoglycemia injury earlier and with better accuracy and specificity.
Based upon the present understanding of cellular pathogenetic
events of hypoglycemia, future phosphate MRS studies will
probably be able to delineate simultaneous alterations in
adenosine triphosphate-high energy phosphorous vs. lactate
concentrations. Hypoxic ischemic encephalopathy would be ex-
pected to reduce ATP-high energy phosphorous and elevate lactate,
whereas HGE would be expected to demonstrate reduced ATP-high
energy phosphorous without lactate elevation. Hence, an ATP-high
energy phosphorous/lactate ratio may be useful in categorizing
acute or subacute hypoglycemia brain injury and correlating with
late sequelae.
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No. of patients (%)
Neuroimaging findings
17 (100%)
Occipital lobe involvement 14/17 (82%)
Dilatation of brain lateral ventricles 7/17 (41%)
Parietal lobe involvement 5/17 (29%)
Other brain parts involvement 2/17 (12%)
Neurologic sequelae
Seizures as presenting symptom 12/17 (70%)
Motor and/or psychodevelopmental delay 11/17 (65%)
Visual impairment 7/17 (41%)
Microcephaly 6/17 (35%)
Hypoglycemia findings
PGL (mg/dl) when hypoglycemia was first detected
Median
Range
7 mg/dl
2±26 mg/dl
Postnatal time (hrs) when hypoglycemia was first
detected
Median
Range
48 hrs
1±72 hrs
MRS = magnetic resonance spectroscopy
ATP = adenosine triphosphate
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Correspondence:
Dr. A.L. Alkalay, Director of Well Baby Nursery,
Division of Neonatology, Dept. of Pediatrics, Ahmanson Pediatric
Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Room 4310,
Los Angeles, CA 90048, USA.
Phone: (1-310) 423-4434
Fax: (1-310) 423-2114
email: arie.alkalay@cshs.org
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