Neonatal Encephalopathy in Foals

David M. Wong, DVM, MS, DACVIM, DACVECC

Iowa State University

Pamela A. Wilkins, DVM, PhD, DACVIM, DACVECC

University of Illinois

Fairfield T. Bain, DVM, DACVIM, DACVP, DACVECC

Equine Sport Medicine & Surgery, Weatherford, Texas

Charles W. Brockus, DVM, PhD, DACVIM, DACVP

Charles Rivers Laboratory, Sparks, Nevada

Abstract: Neonatal encephalopathy is a common central nervous system disorder of neonatal foals and human infants, resulting in
clinical signs such as lethargy, inappropriate behavior, seizures, and other neurologic deficits. Although neonatal encephalopathy is
frequently seen in equine practice, a paucity of veterinary clinical and basic science research data is available. Therefore, the
pathophysiologic mechanisms of this disorder in equids, such as energy deprivation, excess excitatory amino acids, and free radical
injury, have been extrapolated from human medicine. Equine veterinarians have used various diagnostic and therapeutic regimens
from human medicine with reasonable success in equine patients. Understanding the potential pathophysiologic mechanisms involved
in neonatal encephalopathy can facilitate management of affected foals.

N
eonatal encephalopathy in foals has been associated with
various terms, including neonatal maladjustment syndrome
and hypoxic-ischemic encephalopathy.1 Descriptive terms
such as barker foal, wanderer, or dummy foal have also been
used.2 Regardless of the nomenclature, neonatal encephalopathy
is a common disorder of infants and foals under the broad category
of perinatal asphyxia syndrome. Asphyxia is caused by impaired
oxygen delivery to cells, resulting from hypoxemia or anemia
(decreased oxygen content in blood), while ischemia pertains to
decreased blood perfusion.2,3 Despite the emphasis on a hypoxic-
ischemic event in “hypoxic-ischemic encephalopathy,” hypoxia-
ischemia or asphyxia has not been documented in all infants with
neonatal encephalopathy; this is also true for affected neonatal
foals.4,5 In some of these instances, increased proinflammatory
cytokines associated with placental infection and fetal inflammation
may have played a role in the development of the associated neu-
rologic disturbances; therefore, neonatal encephalopathy may be
a more appropriate term.6,7
Biochemical events associated with hypoxia-ischemia include
energy failure, membrane depolarization, brain edema, excess
concentration of neurotransmitters, production of reactive oxygen
and nitrogen species, and lipid peroxidation, all of which potentially
contribute to brain dysfunction and neuronal death.8,9 Most
information regarding the pathophysiology of neonatal encephal-
opathy is directed at infants. This information has been extrapolated
to equine medicine because equine-specific information on neonatal
encephalopathy in foals is exceedingly sparse. A basic knowledge
of potential pathophysiologic mechanisms in nonequine species
may provide essential information and therapeutics for diagnosing
and treating neonatal encephalopathy in foals.
Pathophysiologic Mechanisms
A combination of biochemical and physiologic events, rather than
a distinct singular event, may contribute to the pathophysiologic
mechanisms associated with neonatal encephalopathy. It has
been proposed that after a reversible hypoxic-ischemic brain insult,
neuronal death occurs in two phases10 (FIGURE 1). The first
phase—primary neuronal cell death—is associated with related
events: cellular hypoxia, energy failure, and cellular membrane
depolarization.10 An initial prevailing theme is energy failure as a
result of oxygen and glucose deprivation to the brain secondary
to hypoxia-ischemia.3,9,11 Oxygen is essential for normal aerobic
energy production via oxidative phosphorylation, with the brain
consuming approximately 20% of total body oxygen.12 The brain
also consumes approximately 25% of total body glucose and
depends on a constant supply of glucose to maintain homeostasis.12
Depletion of ATP, even during mild episodes of hypoxia-ischemia,
may initiate a cascade of events ultimately resulting in neuronal
death.11 More specifically, cell-membrane ion pumps rely on suffi-
cient ATP to function; with decreased availability of ATP, decreased

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 Neonatal Encephalopathy in Foals

Figure 1. Proposed phases of neuronal injury and death in foals with hypoxic-ischemic encephalopathy. (a) Hypoxic-ischemic encephalopathy is associated with primary
(acute) neuronal injury and death related to cellular hypoxia, energy failure, and cellular depolarization. This results in decreased ATP, failure of membrane pumps (Na+-K+,
Ca++), and influx of Na+ and Ca++ into neurons and other cells. Increased intracellular Na+ results in cell swelling, while membrane depolarization contributes to glutamate
release. (B) Secondary neuronal death is associated with excess extracellular glutamate, free radical production, and inflammation. (C) Presynaptic nerve ending and
glutamate receptors within the neuronal cell membrane. Activation of these receptors results in the influx of Na+ (NMDA, AMPA, kainate) and Ca++ (NMDA) into the cell.
Increased intracellular Ca++ causes activation of numerous pathways that can result in cell injury or death. (NMDA: N-methyl-D-aspartate; AMPA: a-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid)

activity of the sodium ion–potassium ion (Na+-K+) pump results
in sodium influx into neurons, membrane depolarization, and
concomitant water entry with subsequent cell swelling.10 In addition,
the excitatory neurotransmitter glutamate accumulates in the
extracellular space as a result of (1) failure of energy-dependent
glutamate uptake into neurons and (2) increased glutamate release
from neurons.8,10 Glutamate then activates receptors within the
central nervous system (CNS), resulting in sodium entry through
ionotropic receptors, passive influx of chloride and water, cell
swelling, and potential cell lysis.8
Conceptually, neuronal cell death from acute energy failure as
a result of a hypoxic-ischemic event is plausible and certainly
contributes to the pathophysiologic mechanisms of neonatal
encephalopathy. However, studies suggest that this explanation is
too simplistic and that a significant amount of neuronal cell death
occurs after termination of the initial hypoxic-ischemic insult.10,13–15
Furthermore, experimental studies suggest that many, if not most,
deleterious effects of previous ischemia are manifested during
the reperfusion phase.3 The second phase of neuronal death—
delayed neuronal cell death—is associated with reperfusion injury
(oxidative stress), excitotoxicity, accumulation of intracellular
calcium, activation of numerous enzymes and pathways, cytotoxic
actions of activated microglia, inflammation, and apoptosis10
(FIGURE 1). Many of the pathophysiologic mechanisms of delayed
neuronal cell death are initiated during the acute hypoxic-ischemic
insult, but the detrimental effects manifest hours to days after the
initial insult.9 In addition to allowing influx of sodium into the
neuron through specific receptors, excess extracellular glutamate
results in considerable influx of calcium into neurons through
specific glutamate receptors. Increased intracellular calcium is also
a result of energy-dependent calcium pump failure and opening
of voltage-dependent calcium channels.9 Increased intracellular
calcium is very detrimental to neurons and other cells, has been
implicated as a major contributor to neonatal encephalopathy

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and ischemia-reperfusion injury, and is associated with calcium-
dependent activation of various pathways, cell or neuron swelling,
injury, and/or death.8,11 In healthy animals, cells regulate calcium
at very low and nonfluctuating intracellular concentrations because
calcium serves as a secondary messenger necessary for numerous
intracellular reactions. Very small increases in intracellular calcium
can result in activation of phospholipases, proteases, nucleases,
endonucleases, and nitric oxide synthase (NOS); increases in
neurotransmitter release (glutamate); uncoupling of oxidative
phosphorylation; and generation of free radicals, all of which poten-
tially contribute to neuronal cell death via necrosis or apoptosis.4,8,11
Specific Mechanisms of Cell Injury
The Role of Excitatory Amino Acids and Neurotransmitters
Glutamate is a primary excitatory amino acid neurotransmitter
of the CNS, initiating downstream events through its interaction
with various specific receptors, including receptors of N-methyl-
d-aspartate (NMDA), kainate, and α-amino-3-hydroxy-5-methyl-
4-isoxazolepropionic acid (AMPA).8,16 These receptors are linked
to ion channels and are therefore called ionotropic receptors. The
NMDA receptor is linked to calcium channels, while the AMPA
and kainate receptors are linked to sodium channels3 (FIGURE 1).
In healthy animals, interaction between glutamate and these
receptors occurs with vision, learning, and memory; however,
when this interaction is associated with hypoxic-ischemic insults,
it can result in neurodegeneration.16 In healthy animals, glutamate
is released from presynaptic nerve terminals when neuronal de-
polarization occurs.16 Subsequently, glutamate is quickly removed
from the synaptic cleft by glutamate transporters in local astroglia
and converted to glutamine before being transported back into
nerve terminals for reuse.16 Hypoxia or ischemia impairs function
of astroglial glutamate transporters in the synaptic cleft.4,16,17 Impaired
glucose delivery to the brain, associated with ischemia, further
inhibits glutamate transporters that are normally fueled by glucose
metabolism.16 Thus, hypoxic-ischemic insults can significantly
disrupt excitatory synapse function, resulting in accumulation of
extracellular glutamate and associated opening of ion channels
operated by glutamate receptors.17,18 This excitotoxicity—in which
excessive activation of glutamatergic neurotransmission results
in neuronal flooding with intracellular calcium—can subsequently
result in neuronal damage and cell death.4,17 Modification of the
NMDA receptor to allow increased calcium influx further con-
tributes to excessive intracellular calcium when a developing
brain is subject to hypoxia.8,17,19
Cumulatively, a hypoxic-ischemic insult results in accumulation
of extracellular glutamate, activation of calcium channels (primarily
NMDA channels), and, ultimately, increased intracellular influx
of calcium into neurons.8 Consequently, increased intracellular
calcium activates enzymatic pathways involved in the production
of reactive oxygen species (ROS), including the conversion of
xanthine dehydrogenase to xanthine oxidase, activation of NOS,
and activation of phospholipase A2.9 Furthermore, increased
intracellular calcium activates aforementioned cellular pathways
(lipases, proteases, nucleases) and the expression of apoptotic
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Neonatal Encephalopathy in Foals
and antiapoptotic genes, all contributing to cell injury and/or
death.16,20
The Role of Free Radicals
The brain is very susceptible to oxidative damage because it contains
low concentrations of endogenous antioxidants and high concentra-
tions of polyunsaturated fatty acids that are vulnerable to lipid
peroxidation.9 In addition, free radicals can activate specific “death
genes,” resulting in apoptotic cell death of neurons.21 Reperfusion
injury is an important factor responsible for brain injury in
asphyxiated infants via increased production of ROS and nitric
oxide (NO).22 Sources of free radical production include the mito-
chondrial electron transport system, xanthine oxidase, infiltrating
neutrophils and microglia, the action of cyclooxygenase and
lipoxygenase on arachidonic acid, and metabolites of NO3; many of
these pathways are initiated by calcium-activated processes.3
Various studies have clearly documented an increased presence
of ROS during experimental models of human neonatal enceph-
alopathy.22,23 In comparative studies in infants, higher concentrations
of malondialdehyde were measured in plasma and cerebrospinal
fluid from infants with neonatal encephalopathy, indicating
increased lipid peroxidation.22,23 In addition, higher plasma concen-
trations of nitrate and/or nitrite (markers of NO) were detected.22
Furthermore, increased blood-brain barrier permeability was
associated with increased severity of neonatal encephalopathy,
suggesting more severe disruption of the blood-brain barrier in
severe neonatal encephalopathy.22
Particular attention should be directed at the important role of
NO in neonatal encephalopathy and ischemia-reperfusion injury. Of
the three forms of NOS (i.e., constitutive neuronal form [nNOS],
constitutive endothelial form [eNOS], and inducible form [iNOS]),
the constitutive forms are activated by calcium. Specifically, in
neurons, nNOS is localized with NMDA receptors and activated by
calcium influx through the NMDA receptor.8,16 In addition, nNOS
can be upregulated by hypoxia24 and ischemia.25 Increased expression
of nNOS occurs during the hypoxic-ischemic insult via activation of
NMDA receptors and subsequent influx of calcium.4,26 During
reperfusion and reoxygenation, nitric oxide radicals can be gen-
erated; subsequently, the highly toxic peroxynitrite can form and
contribute to cellular injury.9,27,28 Collectively, reactive oxygen and
nitrogen species significantly contribute to neuronal damage by
inducing lipid peroxidation of cell membrane phospholipids that
consequently break down cell membrane integrity.
The Role of Inflammation and Cytokines
The inflammatory response and proinflammatory cytokines are also
involved in the pathogenesis of neonatal encephalopathy.3,9,29,30
Microglial cells, the resident macrophages within the CNS, can be
activated by hypoxic-ischemic insults (specifically by excitatory
amino acids and leukocyte migration) and subsequently produce
proinflammatory cytokines such as interleukin (IL)-1β, IL-6, and
IL-18 as well as tumor necrosis factor α (TNF-α).29–31 The ensuing
inflammatory response increases regional cerebral blood flow
and alters neuronal and microglial function, resulting in brain
E3

injury and cytotoxic edema.29 The inflammatory response also
involves the upregulation of cellular adhesion molecules through
endothelial cells by IL-1 in the brain’s blood vessels, resulting in
the infiltration and accumulation of neutrophils initially, followed
by mononuclear cells.32 These inflammatory cells subsequently
produce ROS and additional inflammatory cytokines, further
contributing to cellular injury. Inflammatory cytokines also activate
iNOS, which is associated with astrocytes and microglia, in a
calcium-independent manner, resulting in further NO production.3,9
Concurrently, TNF-α activates microglial cells and may have
direct cytotoxic effects on the CNS.30,31 Cytokines may injure white
matter by inhibiting differentiation of developing oligodendrocytes,
inducing oligodendroglial apoptosis, and causing myelin degen-
eration, thus exacerbating neuronal injury.9,29 Conversely, beneficial
roles of inflammatory cytokines include activation of cells, such
as neutrophils and microglia, that subsequently eliminate cellular
debris and contribute to functional recovery.30,32 Thus, the in-
flammatory response subsequent to hypoxic-ischemic insults is
necessary to remove cellular debris but may concomitantly result
in cellular injury.
Some cases of “hypoxic-ischemic encephalopathy” show no
evidence of a hypoxic-ischemic event. A theory regarding this type
of neonatal encephalopathy points to possible involvement of the
fetal systemic inflammatory response, in which proinflammatory
cytokines (IL-1, IL-6, TNF-α) are produced by the fetal immune
system in association with intrauterine infections (i.e., placentitis,
chorioamnionitis).6,7,33 In turn, fetal proinflammatory cytokines may
play a role, through unknown mechanisms, in the pathophysiologic
mechanisms associated with neonatal brain injury.33 Studies have
correlated increased proinflammatory cytokines with CNS lesions
in neonatal infants.6,33 In one study involving neonatal infants for
whom the maternal history included chorioamnionitis, there
was a direct relationship between abnormal results of a neurologic
examination and IL-6 concentrations.6 Furthermore, infants with
the most extreme neurologic examination results had the highest
concentrations of IL-6 and IL-8, suggesting that cytokines may
play a role in the cascade of events leading to periparturient brain
injury.6 Proposed mechanisms by which increased proinflammatory
cytokines may damage the CNS include direct cytotoxic effects;
increased blood-brain barrier permeability; increased production
of NOS, cyclooxygenase, and free radicals; increased release of
excitatory amino acids; and induction of systemic inflammatory
response syndrome, resulting in the deleterious effects associated
with inflammation as described above.6,33 Placentitis in pregnant
mares is not uncommon and is a risk factor for the development
of acute neurologic deficits in neonatal foals2; therefore, it is plausible,
but not yet confirmed, that a fetal inflammatory response may
play some part in the pathophysiologic development of neonatal
encephalopathy in foals.
Causes and Clinical Signs
Multiple peripartum conditions have been associated with neonatal
encephalopathy in people. These conditions include severe uterine
asphyxia as a result of reduced uterine or umbilical circulation,
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Neonatal Encephalopathy in Foals
Box 1. Causes of Perinatal Asphyxia Syndrome and/or
Neonatal Encephalopathy in Foals
Maternal Factors Fetal Factors
• Dystocia • Meconium aspiration
• Induced parturition • Twin foals
• Cesarean section • Fetal infection
• Placentitis • Congenital malformations
• Premature placental separation • Umbilical cord accidents
• Severe illness
• Surgery
• Postterm pregnancy (fescue
toxicity)
• Normal parturition
• Hypotension/impaired tissue
oxygenation
—Endotoxemia
—Hemorrhage
—Anemia
—Severe respiratory disease
postnatal respiratory insufficiency, and severe cardiac malforma-
tions.9,34 Clinical signs of neonatal encephalopathy in infants vary
with the severity of the insult. Signs associated with an acute hypoxic-
ischemic insult include depressed consciousness, abnormal re-
spiratory patterns, bradycardia, and severe seizures.4,16,17,34 The acute
phase occurs in the first 12 hours after insult and is typically followed
by a latent period, lasting hours to days, in which mental alertness
may transiently improve before encephalopathic signs (e.g., seizures,
respiratory arrest, hypotonia, inability to feed orally, deep stupor
or coma) are observed at 24 to 72 hours of age.4,16,34 Infants who
survive to 72 hours of age usually improve over the next several
days to weeks; however, certain neurologic deficits (e.g., mild to
moderate stupor; abnormalities of sucking, swallowing, and
tongue movements) may persist.34
Many parallels in causes and clinical signs of neonatal enceph-
alopathy exist between infants and foals. Conditions associated
with peripartum asphyxia in foals include dystocia, induced par-
turition, cesarean section, placentitis, premature placental separation,
meconium aspiration, twin foals, fetal infection, severe maternal
illness, maternal surgery, and postterm pregnancies; alternatively,
neonatal encephalopathy in foals can be associated with normal
parturition2,35–37 (BOX 1). In a retrospective study of 78 neonatal foals
with a primary diagnosis of neonatal encephalopathy, historical
information revealed the presence of placental abnormalities
(55% of foals), gestational problems (21%), premature placental
separation (34%), and dystocia (30%).38 Foals with neonatal
encephalopathy may appear healthy at birth but exhibit CNS
abnormalities within hours of birth to 1 to 2 days of age.36–38 Clinical
E4

Box 2. In the Field: Failure of Passive Transfer
Neonatal foals are immunocompetent at birth but immunologically naïve,
having minimal immunoglobulins and no memory responses associated
with adaptive immunity. Therefore, neonatal foals require consumption of
antibody-rich colostrum to acquire immediate protection against various
pathogens within the environment. In certain instances, neonatal consumption
of adequate colostrum does not occur, resulting in failure of passive transfer
(FPT) of maternal antibodies. These instances include maternal factors
(e.g., rejection of the foal, agalactia, inadequate colostrum quality or quantity,
premature lactation, maternal death during parturition) or neonatal factors
(e.g., prematurity, sepsis, musculoskeletal disorders, neurologic disorders).
The incidence of sepsis and related complications increases dramatically in
foals with FPT. FPT can be diagnosed using various tests that quantitatively or
semiquantitatively measure the concentration of IgG in whole blood, plasma,
or serum. One of the more practical semiquantitative diagnostic tests for FPT
is the ELISA (SNAP Foal IgG Test Kit, IDEXX Laboratories). In this test, the
foal’s blood, plasma, or serum is mixed with reagents within the test device,
resulting in color development of the test sample area. The intensity of color
change is proportional to the IgG concentration in the foal’s sample. The color
change of the foal’s sample is compared with calibrated IgG concentrations of
400 and 800 mg/dL. A color change representing an IgG concentration >800
mg/dL indicates adequate passive transfer, 400 to 800 mg/dL indicates partial
FPT, and <400 mg/dL indicates complete FPT. Neonatal foals should be
administered antibodies if complete FPT is identified. If a foal is younger
than 12 hours, good-quality colostrum or equine plasma can be administered
orally. At least 2 L of good-quality equine colostrum, divided into 300- to
500-mL increments, should be administered orally within the first 12 hours
after birth. The ability of the small intestine to absorb colostrum decreases if
antibodies have not been ingested within 6 hours after birth. If the foal is older
than 12 hours, the ability of the small intestine to absorb antibodies through
pinocytosis is greatly reduced or absent. Thus, plasma must be administered
intravenously through tubing equipped with an inline filter. Observation for
signs of a transfusion reaction, such as fever, tachycardia, tachypnea, or
urticaria, is warranted. A starting dose of plasma to treat FPT is 1 to 2 L in a
50-kg foal, but the IgG concentration should be rechecked after plasma or
colostrum administration to ensure that adequate antibodies have been
administered to the foal. Similar recommendations are made in ill foals with
IgG concentrations of 400 to 800 mg/dL. Foals with an IgG concentration of
400 to 800 mg/dL that are in a clean, well-managed facility and are clinically
healthy may not require treatment, and their IgG levels are usually not
rechecked later. Evaluation of passive transfer should be considered in all
neonatal foals because of the prevalence of FPT and the severe complications
associated with it.
signs in foals vary greatly and can include one or more of the
following: weakness (hypotonia), mental depression (stupor,
somnolence, difficult to arouse, coma), mild to severe seizure activity,
tremors, and hypertonia.2,35–38 Other clinical signs include inability
to find the udder, inappropriate nursing behavior, loss of suckle
reflex, loss of affinity for the dam, loss of recognition of the envi-
ronment, abnormal vocalization, dysphagia, weak tongue tone,
central blindness, irregular respiratory pattern (apnea, abnormally
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Neonatal Encephalopathy in Foals
slow respiratory rate), and proprioceptive deficits.2,35–38 While this
article focuses on damage to the CNS, perinatal asphyxia can injure
multiple systems. In one review of perinatal asphyxia in infants,
organ dysfunction of the CNS was most frequently documented
(82%), followed by dysfunction of the renal (42%), cardiac (29%),
gastrointestinal (29%), and pulmonary (26%) systems.39 Thus, a
detailed systematic examination of foals with neonatal encephal-
opathy is warranted.
Diagnosis
Diagnosis of neonatal encephalopathy in infants is based on his-
torical information, neurologic examination, and supplementary
diagnostics, including electroencephalography and brain imaging
studies (computed tomography, magnetic resonance imaging).34
In foals, many of the noted clinical signs can occur with other
conditions, including neonatal sepsis, hypoglycemia, and prema-
turity. Therefore, neonatal encephalopathy in foals may occur as
a primary problem or can complicate other clinical conditions.
Diagnostics such as a complete blood count, serum biochemistry,
arterial blood gas analysis, blood culture, urinalysis, and assessment
of passive transfer of maternal antibodies (BOX 2) may be considered
to identify other neonatal disorders and evaluate other body systems
involved. Diagnosis of neonatal encephalopathy in foals relies on an
accurate history, identification of neurologic deficits, and exclusion
of other causes of CNS deficits, such as infectious, congenital,
metabolic, or developmental conditions. Although no specific
clinicopathologic findings have been highly suggestive of neonatal
encephalopathy in foals, in the aforementioned study38 of foals
with neonatal encephalopathy, 32% had an increased serum crea-
tinine concentration, while 61% had an increased serum creatine
kinase concentration. In addition, increases in the serum creatinine
concentration (>3.5 mg/dL) and/or a low presuckle blood glucose
concentration (<35 to 40 mg/dL) have been associated with placental
insufficiency and an increase in neonatal encephalopathy.2 Hypox-
emia, hypercarbia, acidemia, and hypocalcemia may also be observed
in foals with perinatal asphyxia, although these clinicopathologic
abnormalities can arise from other neonatal disorders.5,35
A recent equine study40 evaluated the usefulness of two bio-
markers of brain injury, ubiquitin C-terminal hydrolase 1 (UCHL1)
and phosphorylated axonal forms of neurofilament H (pNF-H), as
potential antemortem diagnostic biomarkers of neonatal encephal-
opathy. In this retrospective study, UCHL1 and pNF-H from the
plasma of 31 foals with a clinical diagnosis of neonatal encephal-
opathy were compared with those of 17 healthy foals. The authors
reported that UCHL1 was significantly better than pNF-H for
diagnosing neonatal encephalopathy.40 Specifically, the median
concentration of UCHL1 (6.57 ng/mL; range: 2.35 to 11.90 ng/
mL) was significantly higher in foals with neonatal encephalopa-
thy compared with the median concentration in healthy foals
(2.53 ng/mL; range: 1.4 to 4.01 ng/mL).40 The reported sensitivity
and specificity of UCHL1 for diagnosing neonatal encephalopathy
were 70% and 94%, respectively.40 Measurement of UCHL1 is not
readily available at this time, and further study is necessary to
determine the usefulness of this biomarker.
E5
 Neonatal Encephalopathy in Foals

Table 1. Potential Therapeutics for Foals With Perinatal Asphyxia Syndrome

Body System Dose Comment or Reference
Central nervous system: perform regular neurologic examinations
Control of seizures
Diazepam 0.1–0.4 mg/kg IV, as needed
Phenobarbital 2–10 mg/kg IV q12h for persistent seizures Monitor serum concentrations
Pentobarbital 2–10 mg/kg IV
Midazolam 0.04–0.1 mg/kg IV, as needed 50 mg added to 90 mL of 0.9% NaCl produces a 0.5-mg/
0.02–0.06 mg/kg/h CRI for persistent seizures mL solution
NMDA antagonists
Magnesium sulfate 0.05 mg/kg/h IV CRI, loading dose
0.025 mg/kg/h IV CRI, maintenance dose
Reduction of CNS edema
Mannitol 0.25–1.0 g/kg IV as a 20% solution over 20 min, q12–24h Contraindicated if cerebral hemorrhage is present
Dimethyl sulfoxide 0.5 g/kg IV as a 10% solution over 30–60 min, q12–24h
Free radical scavengers/antioxidants
Vitamin E 5000 IU PO q24h
Vitamin C 100 mg/kg/d IV
Thiamine 10 mg/kg IV
Dimethyl sulfoxide 0.5 g/kg IV as a 10% solution
Allopurinol 44 mg/kg PO within first 4 hr
Respiratory system: monitor arterial blood gas (Pao2, Paco2, pH, HCO3 -)
Hypoxemia
Intranasal O2 3–5 L/min humidified oxygen Maintain patient in sternal recumbency
Hypercapnia
Doxapram 0.02–0.05 mg/kg/h CRI May be more effective than caffeine
Caffeine 10 mg/kg PO or per rectum, loading dose;
2.5 mg/kg PO or per rectum, as needed
Persistent/severe hypoxemia and hypercapnia
Mechanical ventilation — Palmer JE. Ventilatory support of the critically ill foal. Vet
Clin North Am Equine Pract 2005;21(2):457-486.
Surfactant replacement Consider if surfactant dysfunction or deficiency is suspect
Antiinflammatory medications
Pentoxifylline 10 mg/kg PO q12h Specific pharmacologic information not available for foals
Renal system: monitor urinalysis, urine output, body weight, and fractional excretion of electrolytes in urine; medications may not be very helpful; it is
important to give IV fluids judiciously
Fenoldopam 0.04 µg/kg/min CRI Dopamine-1 receptor agonist
Furosemide 0.5–1.0 mg/kg IV q8–12h Monitor serum electrolytes
0.12 mg/kg IV, loading dose; 0.12 mg/kg/h CRI
Mannitol 0.5–1.0 g/kg IV as a 20% solution over 20 min Osmotic diuretic

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 Neonatal Encephalopathy in Foals

Table 1. Potential Therapeutics for Foals With Perinatal Asphyxia Syndrome (cont.)
Body System Dose Comment or Reference
Cardiovascular system: monitor indirect or direct blood pressure, blood lactate level, and fluid therapy (body weight, central venous pressure)
Dopamine 2–5 µg/kg/min CRI (as an inotrope) Monitor heart rate and rhythm and blood pressure
5–10 µg/kg/min CRI (as a vasopressor)
Dobutamine 1–3 µg/kg/min CRI Monitor heart rate and rhythm and blood pressure
Norepinephrine 0.1–1.5 µg/kg/min CRI Monitor heart rate and rhythm and blood pressure
Corley54
Fluid therapy 2–5 mL/kg/h IV, maintenance rate Evaluate fluid therapy frequently
Palmer53
Gastrointestinal system: place nasogastric tube to evaluate for gastric reflux; if gastric reflux is significant, delay feeding and provide parenteral nutrition
Antiulcer medication/gastrointestinal protectants
Sucralfate 20–40 mg/kg PO q6h
Omeprazole 4 mg/kg PO q24h Not labeled for foals younger than 4 weeks of age, but
frequently used in neonates
Bismuth subsalicylate 0.5–4.0 mL/kg PO q6–24h
Prokinetic medication
Erythromycin 0.1–1.0 mg/kg/h CRI
Lidocaine 1.3 mg/kg slow IV, loading dose; 0.05 mg/kg/min CRI
Metoclopramide 0.1–0.3 mg/kg IV over 30 min q6h Koenig J, Cote N. Equine gastrointestinal motility—
0.04 mg/kg/h CRI ileus and pharmacological modification. Can Vet J
0.1–0.25 mg/kg PO q6h 2006;47(6):551-559.
Nutritional Support: avoid enteral feedings if gastric reflux is significant
Enteral feeding Mare’s milk: feed 10% to 25% of foal’s body weight per
day; divide into every-other-hour feedings
Parenteral nutrition 10 g/kg/d of dextrose; 2 g/kg/d amino acids; 1 g/d of lipids Starting formula provides 53 kcal/kg
Hypoglycemia
Dextrose 4–8 mg/kg/min CRI Avoid hyperglycemia
Buechner-Maxwell VA. Nutritional support for neonatal foals.
Vet Clin North Am Equine Pract 2005;21(2):487-510.
Correction of metabolic derangements and prevention of secondary infection
Metabolic acidosis Provide NaHCO3- supplementation only after foal has been May cause hypernatremia or hypokalemia
properly hydrated with balanced IV crystalloid solution
Electrolyte derangements Correct electrolyte derangements with oral or IV
supplementation
Prophylactic antimicrobials Consider administering broad-spectrum antimicrobials Haggett EF, Wilson WD. Overview of the use of antimicrobials
(i.e., ceftiofur, amikacin [monitor for concurrent or for the treatment of bacterial infections in horses. Equine
developing renal injury]) Vet Educ 2008;20(8):433-447.
Corley KTT, Hollis AR. Antimicrobial therapy in neonatal
foals. Equine Vet Educ 2009;21(8):436-448.
Ensure adequate passive transfer of maternal antibodies
Administer plasma and colostrum If there is failure of passive transfer

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Treatment
Treatment of neonatal encephalopathy in foals and infants is
principally supportive and should address the multiple organ
systems that may be involved in perinatal asphyxia. TABLE 1 outlines
therapeutics used to treat foals with neonatal encephalopathy.
This section discusses therapeutics and medications that target
specific pathophysiologic mechanisms in infants with neonatal
encephalopathy. Because energy depletion plays a role in the
development of neonatal encephalopathy in infants, and because
neonates have minimal energy reserves, it is imperative to maintain
the blood glucose concentration within the reference range.11
Maintenance of adequate blood pressure and perfusion is also
vital for supporting cerebral perfusion and avoiding further ischemic
injury.34 This can be accomplished by identifying cause(s) of
hypotension and cautiously administering intravenous fluid therapy
and vasopressors and/or inotropes, if necessary. Systemic hyper-
tension should be avoided because it may result in rupture of
cerebral capillaries and hemorrhagic complications.34 In addition,
strategies to decrease the cerebral metabolic rate to preserve
energy have been investigated in infants. The most promising
therapy is mild hypothermia; high doses of barbiturates or mild
hypercapnia have also been suggested to decrease energy use.9,11
Hypothermia may also inhibit glutamate release from synaptic
nerve endings, improve uptake of glutamate by astrocytes, reduce
free radical production and NO synthesis, and decrease cortical
cytotoxic edema.9,11 Mannitol has been used to reduce cerebral
edema, but improved outcome has not been demonstrated in
infants administered mannitol, perhaps because the edema may be
intracellular.41,42 While seizure activity may arise from pathophys-
iologic processes involved in neonatal encephalopathy, seizure
activity can greatly increase cerebral oxygen consumption and
contribute to ongoing injury.43 Therefore, anticonvulsants (pheno-
barbital, diazepam, midazolam) are implemented if seizures are
observed in infants.
Accumulation of glutamate appears to contribute to the patho-
genesis of neonatal encephalopathy; thus, inhibition of glutamate
release has been targeted. Because calcium influx is necessary for
glutamate release at presynaptic nerve endings, calcium-channel
blockers (flunarizine, nimodipine) have been administered to
circumvent glutamate release in infants.11,43 Magnesium has also
been administered to block the release of glutamate.11,43,44 Specific
NMDA-receptor antagonists (e.g., dizocilpine, magnesium,
ketamine, dextrorphan) have also been investigated.9,11,43 In efforts
to abate cerebral inflammation associated with neonatal enceph-
alopathy, medications that inhibit the inflammatory process (e.g.,
IL-1 antagonists, anticytokine antibodies, platelet activation factor
antagonists, pentoxifylline) have also been investigated.11,43
Inhibiting free radical production with medications (e.g.,
allopurinol, iron chelators, superoxide reductase, 21-aminosteroids,
dimethyl sulfoxide [DMSO]) or antioxidants (e.g., vitamins E
and C) has also been considered in infants.11,43 Older studies using
animal models have suggested that endogenous opiates may neg-
atively influence ventilation of neonates with perinatal asphyxia.45
Based on this theory, naloxone, an opiate antagonist, may improve
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Neonatal Encephalopathy in Foals
outcomes for newborn infants with perinatal asphyxia.45,46 However,
reviews of this treatment have not provided adequate evidence
that naloxone improves outcomes.46,47
Alternatively, recent research has suggested neuroprotective
effects of hyperbaric oxygen in rat models of neonatal encephal-
opathy by, among other mechanisms, reducing apoptosis,
promoting proliferation of neuronal stem cells, enhancing oxy-
gen radical scavengers, and increasing oxygen delivery to the
brain.48,49 Furthermore, the use of hyperbaric oxygen in infants
has demonstrated increased activity of superoxide dismutase;
decreased levels of malondialdehyde, NO, and NOS; and improved
neurologic assessments.50
While several of the aforementioned therapeutics have not
been used in the veterinary clinical setting or are cost-prohibitive
in equine medicine, several are readily available and have been used
in foals (TABLE 1). In foals, single seizures can be controlled with
diazepam; however, phenobarbital or, less commonly, midazolam
may be considered for controlling repeated seizure activity.51,52 A
normal blood glucose concentration can be maintained in foals
by constant-rate infusion of dextrose, but hyperglycemia or hy-
poglycemia should be avoided.53 Preservation of adequate blood
pressure through judicious administration of intravenous fluid
therapy and vasopressors and/or inotropes is also readily achievable
for neonatal foals.53,54 Investigation of the pharmacokinetics of
pentoxifylline in adult horses has revealed that administration
of this medication may inhibit TNF-α production in foals with
neonatal encephalopathy.55 Additionally, a CRI of magnesium
sulfate has been administered to foals in an effort to block calcium
influx and, subsequently, release of glutamate.51,56 Antioxidants
such as vitamins E and C can be administered along with thia-
mine to support cellular metabolism, including mitochondrial
metabolism and Na+-K+ ATPases.35,51,56 DMSO is an inexpensive
free radical scavenger that has been used in foals with neonatal
encephalopathy, but the efficacy of this treatment is debatable.35,51
Allopurinol, a xanthine oxidase inhibitor, can be administered to
decrease free radical formation.56 Allopurinol is one of the few
medications that has demonstrated improved neurologic out-
come in prospective clinical studies in infants.57,58 Mannitol has
been used in foals with severe neonatal encephalopathy in an
attempt to reduce edema of the CNS, but this medication may
not be beneficial for treating intracellular (cytotoxic) edema, which
occurs with this disease.2,34,35,52 Naloxone has been suggested as a
therapeutic agent, but its use is very limited in equine neonatal
encephalopathy, as is evidence for its efficacy.51 The use and avail-
ability of hyperbaric oxygen therapy in equine medicine are limited,
but this therapy has been used to treat neonatal encephalopathy
in foals.59
Because there is no specific information regarding the out-
comes of the above therapies for treating neonatal encephalopathy
in foals, use of these therapies remains entirely speculative. Ther-
apeutic objectives in foals with neonatal encephalopathy should
include good supportive/nursing care, correction of clinico-
pathologic alterations, and medications that support or target
alterations in specific organ systems, when applicable (TABLE 1).
E8

Prevention
As noted in BOX 1, specific risk factors for the development of
neonatal encephalopathy in foals have been identified, raising
the question of potential prevention or amelioration in high-risk
fetuses/foals with one or more predisposing factors. The clinician can
first attempt to appropriately treat maternal disease (i.e., placentitis),
if it is identified, before parturition. In addition, observation and
intervention (if necessary) during parturition in mares with risk
factors are important in attempting to prevent neonatal enceph-
alopathy. Furthermore, recognizing distress in neonatal foals is
vital for initiating appropriate therapy, such as cardiopulmonary
cerebral resuscitation or respiratory support. Deliberate and
mandatory obstetric training of midwives, obstetric medical staff,
and house officers in one hospital decreased the incidence of
neonatal encephalopathy from 27.3% to 13.6%, highlighting the
significance of adequate training and prompt recognition and
intervention of fetal or neonatal compromise in infants.60
Several detailed veterinary reviews are available regarding
recognition of fetal compromise and equine neonatal resuscitation.61,62
No clinical trials have specifically investigated prevention of neonatal
encephalopathy in foals, but proposed measures to prevent neonatal
encephalopathy in other species include administering myriad
medications and inducing hypothermia immediately after birth.
However, a fine and perhaps ambiguous line separates prevention
and treatment of neonatal encephalopathy. Of these reviews of
various trials, only a few modalities have had encouraging results.
Therapeutic hypothermia in animal studies and infants has been
associated with significant and clinically important reductions in
mortality and neurodevelopmental disability.63 However, this
modality has not been explored in equine medicine. In another
study, a significant decrease in neonatal seizures was documented
in infants with neonatal encephalopathy who were administered
phenobarbital (20 mg/kg IV) within 6 hours of birth; however,
mortality and neurologic outcome were not altered.64 Reviews
of randomized, controlled studies using glutamine, naloxone,
dopamine, and other medications have not provided sufficient
evidence to advocate the use of these medications for preventing
neonatal encephalopathy or improving patient outcome.47,65,66
A potential preventive therapy that is under investigation
involves modifying the steroidal environment of the fetal and
neonatal brain. Recent studies have demonstrated that the brain
is able to form steroids de novo (neurosteroids) that have a pro-
tective role and may prevent neonatal encephalopathy.67,68 More
specifically, the allopregnanolone concentration is notably high
in a healthy fetal brain and dramatically declines at birth.67,68 The
high allopregnanolone level has a suppressive effect on the CNS
(producing sleep-like behavior) during fetal life.67 However, the
decrease in the allopregnanolone level after birth may increase
the susceptibility of newborns to brain injury.67 The neuroprotective
effects of neurosteroids are thought to result from γ-aminobutyric
acid (GABAA) receptor–mediated hyperpolarization, leading to a
general reduction in CNS excitation.67 Acute hypoxia results in
increased allopregnanolone synthesis in the brain, which may
reduce neuronal cell death following acute asphyxia.67 Conversely,
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Neonatal Encephalopathy in Foals
inhibition of neurosteroid synthesis in the fetal brain increases
cell death.67 Thus, this information suggests that stimulation of
neurosteroid production may protect the fetal brain from asphyxia-
induced CNS injury, possibly serving as a preventive therapy, but
further studies are necessary to explore this relatively new theory.
Prognosis
In general, foals with a primary diagnosis of neonatal encephal-
opathy without complicating factors have a good prognosis, with
survival rates of 70% to 75% in some reports.2,5,37,69 Most foals
that survive appear to recover completely.2,5,37 Subjectively, we
have observed that most foals that survive the initial 5 days of life
and demonstrate neurologic improvement over this period appear
to have a good prognosis and no long-term neurologic deficits.
This supposition is supported by a retrospective review of 78
foals with a primary clinical diagnosis of neonatal encephalopathy,
in which neurologic signs lasted for 1 day in 29 foals, 2 days in 17
foals, 3 days in eight foals, 4 days in four foals, and 5 days in one
foal; 19 foals did not survive.38 Many foals that survive go on to
perform successfully.2,37,70 Foals with a guarded to poor prognosis
include those that have complicating factors (e.g., sepsis), remain
comatose or difficult to arouse, show no improvement in neurologic
function during the first 5 days of life, or demonstrate severe,
recurrent seizures.5,35 Rare, long-term neurologic deficits may
include inability to suckle from the mare’s udder, prolonged visual
impairment, residual spasticity, recurrent seizures, and unusual
docility as adults.5,38
Conclusion
While neonatal encephalopathy is a relatively common CNS disorder
in neonatal foals, information regarding the associated pathophys-
iologic mechanisms in foals is based on information from human
and laboratory animal models. The scientific literature provides
abundant information on neonatal encephalopathy in infants;
equine practitioners must base therapeutic plans on this information
until equine-specific information is available. Addressing the
multiple body systems that may be affected by neonatal enceph-
alopathy in foals is essential for successful therapy. With diligent
supportive and nursing care, foals with neonatal encephalopathy
have a reasonable prognosis for survival.
Disclosure Statement
Dr. Bain discloses that he is coowner and vice president of Equine
Oxygen Therapy.
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