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Neonatal encephalopathy (NE) is a broad term used for foals (and infants) that develop noninfectious neurologic signs in the immediate postpartum period.
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Controversies about equine NE and neonatal malajustment syndrome (NMS) relate to the lack of pathophysiologic information and target-specific therapies, with most mechanistic explanations extrapolated from other species.
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Based on clinical history, clinical signs, postmortem findings, and recent association of NE with neuroactive steroids, it is
Equine Neonatal Encephalopathy: Facts, Evidence, and Opinions
Section snippets
Key points
What concepts can be unified about neonatal encephalopathy?
For decades there has been a tendency to group foals with neurologic signs in the immediate postpartum period under a single umbrella, ignoring a range of pathophysiologic processes that could alter brain cell function in the equine neonate. Most of what is assumed to occur in foals with NE has been extrapolated from animal models or people with various acute brain disorders (stroke, trauma, ischemia, hypoxia, and inflammation). In recent years, however, attention has been placed on endocrine
Comparative pathophysiology
In general terms, the mechanisms of equine NE can be dived into (1) those that are consequence of adverse peripartum events leading to ischemia/hypoxia in the prepartum period (eg, maternal or placental disease), at partum (eg, dystocia and caesarian section), or in the postpartum period (eg, umbilical bleeding/compression/clamping, heart disease, and isoerythrolysis); (2) those in which there is evidence or a history of placental disease (placentitis or placental separation) with variable
Pathophysiology of ischemia/hypoxia
The pathophysiologic principles of CNS ischemia and hypoxia are shared by animals and people. Therefore, it can be assumed that information generated in other species applies to newborn foals with ischemic encephalopathy but may not apply to foals in which the nature of the neurologic signs is unknown or unrelated to ischemia or hypoxia. The unique endocrine profile of the equine pregnancy is another factor that in the context of foal disorders has been ignored but may play a role in NE.
Inflammation
Hypoxic-ischemic injury in human infants is characterized by microglial activation and infiltration.33 Compared with adults, the microglia in the developing brain respond rapidly to hypoxia by increasing phagocytic activity, releasing proinflammatory and anti-inflammatory cytokines, proteolytic enzymes, glutamate, NO, and ROS, which, in addition to causing neuronal, glial, and endothelial dysfunction, also disrupt the immature blood-brain barrier (BBB).33 This facilitates cerebral infiltration
Phases of brain injury after hypoxia/ischemia
Chronologically, after an ischemic-hypoxic event, cerebral injury occurs in 3 phases, from early reversible (phases 1 and 2) to irreversible (phase 3) states.35 In phase 1 (primary energy failure; 0–6 hours), neurons are deprived from energy and oxygen, shifting to anaerobic metabolism with lactate accumulation, ATP reduction, Na+, K+-ATPase failure, Na+ and Ca2+ influx, water accumulation, cell swelling, edema, cytokine secretion, initial reperfusion injury, ROS production, and cell death. In
Reperfusion injury
Reperfusion injury or ischemia-reperfusion injury occurs when oxygenation returns after prolonged ischemia. The restoration of tissue oxygenation leads to oxidative damage, oxidative stress, inflammation, cellular dysfunction, and cell death (necrosis and apoptosis). Inflammation is a major component of reperfusion injury. In the CNS, reperfusion injury is a key process during stroke, brain trauma, and ischemia. In response to ischemia, hypoxanthine is produced by xanthine
Cytotoxicity
Cytotoxicity is a broad term (toxic to cells) that refers to cellular damage or cellular death from substances (endogenous and exogenous), imbalances (endocrine/paracrine and electrolytes), energy/oxygen deprivation (hypoglycemia, ischemia, and hypoxia), immune cells (inflammation), or physical/chemical/environmental injuries (trauma, burns, irritants, irradiation, and pressure). Thus, cytotoxicity may be caused by drugs, toxins, neurosteroid imbalances, neurotransmitters (excitotoxicity),
Excitotoxicity
Excitotoxicity denotes neuronal injury and death from excessive exposure to excitatory amino acids. Because glutamate is the main excitatory neurotransmitter in the CNS, excitotoxicity is primarily a consequence of prolonged exposure to glutamate, which results in cation (Na+, Ca2+) entry into brain cells (neurons, astrocytes, and oligodendrocytes). Glutamate is continuously released from neurons and removed by astrocytes in an equilibrium (γ-aminobutyric acid [GABA]-glutamate-glutamine cycle)
The astrocyte and brain energy
Although most literature on cerebral energy deprivation has focused on the neuron, there is evidence that astrocyte dysfunction is a major contributor to neuronal failure.40 Neurons and glial cells have distinct glucose metabolic features, which under normal conditions are coupled (neuron-astrocyte metabolic coupling).43, 44, 45, 46 Aerobic glycolysis and lactate production (Warburg effect) are crucial for energy generation in astrocytes, whereas mitochondrial oxidative phosphorylation
Progestogens, neuroactive steroids, and neonatal brain disorders
Neuroactive steroids (neurosteroids) include steroids de novo synthesized from cholesterol in the nervous system (central and peripheral, by neurons and glial cells) as well as metabolites of steroid hormones from peripheral tissues (adrenal gland, gonads, and placenta).21, 25, 26, 48, 49, 50, 51 The terms, neuroactive steroid and neurosteroid, are used interchangeably; however, technically, neuroactive steroids are products of peripheral steroid hormones metabolized by nervous tissue whereas
Neurosteroid functions
Neuroactive steroids modulate GABAA, NMDA, AMPA, glycine, mPR, and σ1 receptors, promote neurogenesis, synaptogenesis, myelinogenesis, and neuronal plasticity, regulate axon and dendrite growth, alter neuronal excitability, organize neuronal circuits (eg, maternal behavior and fetal brain programming), contribute to glial cell development and function, are neuroprotective, promote energy conservation, modulate the HPAA and the stress response, and are involved in sexual dimorphism.25, 26
Steroids and the developing fetus
Circulating steroids can readily cross the BBB to be converted by neurons and glial cells into neuroactive steroids.63 In primates, placental progesterone is the main substrate for steroids produced in the brain whereas in equids other pregnanes and androstenes are likely metabolized. Neuroactive steroids, in particular allopregnanolone, are very high in the fetal brain.26 Allopregnanolone increases during human pregnancy to promote fetal brain development and programming, to protect from
Endocrinology of the equine placenta and its relevance to neonatal encephalopathy
Fetal, placental, and maternal diseases may contribute to steroid imbalances in the equine neonate. The endocrinology of equine pregnancy is unique compared with other species.68, 69 In the pregnant mare, progesterone and 17α-hydroxyprogesterone concentrations increase and remain elevated until week 25 when they decrease to negligible values.68, 70 As pregnancy advances, other progestogens (pregnenolone, 5α-dihydroprogesterone, and allopregnanolone) rise steadily, reflecting fetal gonad size,
Risk factors
Risk factors for equine NE/NMS are maternal, placental, and fetal in nature. Any maternal condition resulting in systemic inflammation or ischemia/hypoxia can impair perfusion to the uteroplacental unit. Placental diseases (placentitis and placental separation) can potentially lead to NE by interfering with nutrient and oxygen supply to the fetus. However, evidence that placental pathologies are strongly associated with NE/NMS is minimal. Microorganisms can be translocated to fetal circulation
Clinical signs
Documented clinical signs of NE include disorientation, wandering, lack of affinity for the mare, abnormal udder seeking, lack of suckle reflex, suckling on objects, hyperexcitability, ataxia, tremors, star-gazing, chewing movements, dysphagia, head-pressing, arched neck, blindness, tongue protrusion, recumbency, convulsions, recurrent seizures, expiratory noises (barkers), abnormal respiratory patterns, hemorrhagic retina, hypoventilation, and hypothermia.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
Laboratory findings
Reported laboratory abnormalities in foals with NE include hypoxemia, hypercapnia, acidemia, hyperlactatemia, azotemia, hypoglycemia, hypocalcemia, hypomagnesemia, hypermagnesemia, and low thyroid hormone concentrations.7, 8, 10, 15, 20, 21, 23, 77, 78 Most of these abnormalities are secondary to systemic disease (sepsis and hypoperfusion) and organ dysfunction and not a direct manifestation of NE. High total calcium concentration and low alkaline phosphate activity have been linked with
Diagnosis
Determining the cause of NE can be challenging. A diagnosis is reached from the clinical history, clinical signs but more often by exclusion of infectious and congenital conditions.8 As discussed previously, many of these foals appear normal at birth but develop neurologic signs hours later. Laboratory abnormalities reflect perinatal diseases more than NE. Blood markers of brain injury, such as ubiquitin C-terminal hydrolase, have been measured for research purposes but have limited clinical
Treatments, rationale, and evidence of success
Drugs used to treat foals with NE/NMS include diazepam, midazolam, phenobarbital, MgSO4, ketamine, naloxone, doxapram, caffeine, thiamine, ascorbic acid, vitamin E, dimethyl sulfoxide, furosemide, mannitol, allopurinol, fenoldopam, pentoxifylline, hetastarch, hypertonic saline solution, and oxygen insufflation. Hyperbaric oxygen therapy has been used in some cases. Support therapy is necessary and dictated by the clinical presentation, laboratory abnormalities, and prevention of complications.
Necropsy findings
Reported gross findings include congestion, hemorrhage, edema, and necrosis in different regions of the brain. Microscopically, there is swelling, edema, necrosis, and malacia as well as neuronal and glial cell necrosis and apoptosis. Many of these lesions are similar to those seen in animals subjected to experimental ischemia. It is important, however, to mention that neuronal and glial necrosis do not necessarily imply ischemia/hypoxia but could be a result of excitotoxicity or inflammation.
Summary
Equine NE refers to several noninfectious neurologic conditions of newborn foals. Based on clinical history and findings, NE seems to cover different syndromes. The terms NE and NMS do not assume an understanding of the etiology or pathogenesis leading to the clinical presentation of this condition. Ischemia/hypoxia and endocrine imbalances (progestogens, neurosteroids) probably are major contributors to equine NE; however, mechanistic research is necessary to provide corroboration. There are
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Retrospective analysis of factors associated with umbilical diseases in foals
2024, Journal of Equine Veterinary ScienceApgar Score, Clinical, Hemato-Biochemical, and Venous Blood Gas Parameters in a Cohort of Newborn Mule Foals: Preliminary Data
2023, Journal of Equine Veterinary ScienceCorneal Ulcers in Critically Ill Foals in Intensive Care: Case Series of Standard Treatment and Corneal Cross-Linking
2023, Journal of Equine Veterinary ScienceHigh-Risk Pregnancy Is Associated With Increased Alpha-Fetoprotein Concentrations in the Amniotic Fluid and Foal Plasma
2022, Journal of Equine Veterinary ScienceCitation Excerpt :Foals affected by Hypoxic-Ischemic Encephalopathy (HIE) with evidence of dystocic parturition were excluded. Foals with the same clinical presentation but without evidence of a hypoxic insult were classified as affected by Neonatal Syndrome (NS) [24]. Foals were defined as premature when born prior to 320 days of gestation and dysmature when born after 320 days both with immature physical characteristics: low body weight or small for gestational age respectively, inability to maintain body homeostasis and to suckle, hyperextension of flexor tendons in the, or both, incomplete carpal and tarsal bone ossification.
Neurologic Disorders of the Foal
2022, Veterinary Clinics of North America - Equine PracticeCitation Excerpt :A number of specific physiologic mechanisms exist which contribute to this environment, including high concentrations of adenosine (produced from a low oxygen environment), neurosteroids (allopregnanolone, pregnanolone, and androstane), warmth, and minimization of tactile stimulation due to buoyancy in fetal fluids.12–14 Neuroactive steroids have multiple functions including the promotion of neurogenesis, synaptogenesis, myelinogenesis, altering neuronal excitability, modulation of neuronal circuits (involved in maternal behavior and fetal brain programming), are neuroprotective, and modulate the hypothalamic–pituitary–adrenal axis (HPAA) and the stress response.15–17 The neurosteroids interact with gamma-aminobutyric acid (GABA) and N-methyl-d-aspartate (NMDA) receptors in the CNS.
Clinical Outcome of Transcervical Infusion of a Combination of Procaine Penicillin and Gentamicin in Late-term Pregnant Mares
2021, Journal of Equine Veterinary ScienceCitation Excerpt :Neonatal maladjustment syndrome, which is also commonly referred to as neonatal encephalopathy or dummy foal syndrome has been reported to occur in 1%–2% of all live births [18]. Pathogenesis has been suggested to be related to the presence of a combination of perinatal ischemia and hypoxia, reperfusion injury, electrolyte disturbances, and neurosteroid imbalances [19,20]. These mechanisms may occur during periods of maternal illness in the period prior to or during parturition, placental disease such as placentitis or premature separation of the fetal membranes, periods of hypoxia, and/or ischemia during or immediately surrounding parturition or in cases where foaling was uneventful with no known maternal comorbidity present [20].