(Neonatal maladjustment syndrome, Hypoxic ischemic encephalopathy, Barker, Wanderer, Dummy)
Neonatal encephalopathy (NE) is a common, noninfectious CNS disorder of neonatal foals, resulting in clinical signs such as lethargy, inappropriate behavior, seizures, and other neurologic deficits. The condition is associated with the broader syndrome of perinatal asphyxia syndrome, which is believed to result from unrecognized in-utero or peripartum hypoxia, and can injure multiple organ systems. In this context, asphyxia is caused by impaired oxygen delivery to cells, most often resulting from a combination of hypoxemia or anemia (leading to decreased blood oxygen content), and ischemia (decreased blood perfusion).
Species-specific information on the pathogenesis of NE in foals is exceedingly scarce and mostly extrapolated from nonequine species. Primary neuronal cell death may be related to cellular hypoxia, energy failure, and cellular membrane depolarization, whereas 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 apoptosis. In this context, excessive activation of glutamatergic neurotransmission (ie, excitatory amino acids and neurotransmitters), increased production of reactive oxygen and nitrogen species, as well as fetal systemic inflammatory responses with production of pro-inflammatory cytokines (eg, IL-1, IL-6, TNF-α) may all contribute to cell injury and/or death.
Risk factors for perinatal asphyxia may include maternal (eg, respiratory disease, endotoxemia, hemorrhage/anemia, surgery/cesarean delivery), placental (eg, bacterial, fungal- or endophyte-associated placentitis, chronic or acute premature uteroplacental separation), and fetal causes (eg, twinning, congenital abnormalities, dystocia, meconium aspiration, sepsis, prematurity, dysmaturity). Fetal and maternal factors are those that induce hypotension or reduced tissue oxygenation, whereas placental pathology will impair uteroplacental perfusion. Areas of chronic placental separations may thus lead to chronic hypoxia of the fetus. However, the most acute cause of perinatal asphyxia is complete premature placental separation at birth ("red bag" delivery).
CNS signs are most prominent in cases of perinatal asphyxia, but renal, cardiac, GI, and pulmonary systems may also be affected. A detailed, systematic examination of foals with NE is therefore warranted. Renal compromise of foals with NE may present as anuria or oliguria, whereas GI effects of perinatal asphyxia may include colic, transient ileus, meconium impaction, gastric ulcers, gastric reflux, bloat, diarrhea, and necrotizing enterocolitis. Cardiac arrhythmias, edema, poor cardiac output, and systemic hypotension may result from hypoxia of the myocardium. A decrease in pulmonary perfusion may impair surfactant production and lead to ventilation-perfusion mismatch and secondary pulmonary atelectasis. Hepatic and endocrine dysfunction may also be seen. For example, perinatal asphyxia syndrome may cause lower T3 and T4 concentrations in affected foals than in age-matched healthy control subjects.
The neurologic signs of foals with NE are variable and may include weakness (hypotonia), mental depression (stupor, somnolence, difficult to arouse, coma), seizure activity, tremors, and hypertonia. Seizures are relatively common and may range from mildly abnormal movement of the face and jaw to generalized seizures with recumbency and paddling. Other clinical signs include an inability to find the udder, loss of suckle reflex, loss of affinity for the dam, loss of recognition of the environment, abnormal vocalization (hence “barker foals”), dysphagia, weak tongue tone or persistent tongue protrusion, central blindness, opisthotonos, irregular respiratory pattern (apnea, abnormally slow respiratory rate), and proprioceptive deficits. Clinical signs can be asymmetric and may include a head tilt, circling, and asymmetric pupillary reflexes. Foals may appear healthy at birth but often exhibit CNS abnormalities within hours of delivery or by 1–2 days of age. Affected foals are usually afebrile unless secondary infection or sepsis occurs.
Diagnosis is based on compatible clinical findings and exclusion of differential diagnoses. A history of dystocia, premature placental separation, or placentitis may support a diagnosis of NE. The foal’s CBC is usually unremarkable unless sepsis is present. A serum chemistry may also be normal but often indicates organ dysfunction secondary to hypoxic or cytokine-mediated injury. For example, a markedly increased CK concentration may correlate with a recent hypoxic-ischemic muscle insult, whereas an increased GGT concentration can accompany hepatic injury. Transient or spurious hypercreatininemia may indicate adverse maternal and/or placental conditions, or suggest ingestion of creatinine-rich fetal fluids in neonatal foals experiencing periods of peripartum asphyxia. Creatinine in affected foals decreases by >50% within 24 hr of standard neonatal support and generally normalizes within 72 hr. However, if creatinine values remain high, then renal dysfunction must be considered. Hypoxemia, hypercarbia (due to respiratory depression), acidemia, and hypocalcemia may also be seen in foals with NE. CSF may be normal or show an increased RBC count and protein concentration. CNS necrosis, edema, and hemorrhage are found in some cases at necropsy; however, these findings are inconsistent.
Differential diagnoses for NE include bacterial meningitis, equine herpesvirus 1 infection, metabolic abnormalities (eg, hypoglycemia, electrolyte derangements), acid-base disturbances, kernicterus subsequent to massive hemolysis (ie, neonatal isoerythrolysis), brain or spinal trauma, congenital defects (eg, hydrocephalus, hydranencephaly), and nutritional myodegeneration (white muscle disease).
Treatment of NE is primarily supportive. Maintenance of adequate blood pressure and perfusion is vital for supporting cerebral blood flow and avoiding further ischemic injury. This can be accomplished by cautiously administered, goal-directed IV fluid therapy and inotrope or vasopressor support, if needed, while avoiding hypertension. Mild hypothermia, use of barbiturates, and mild hypercapnia have been suggested to decrease cerebral metabolic rate and preserve energy. Because foals have minimal energy reserves, IV glucose administration may be necessary to maintain normal blood glucose concentrations. If the foal is unable to nurse, nutrition can be supplied via an indwelling nasogastric tube. Total parenteral nutrition is indicated in foals with GI dysfunction.
Mannitol (0.25–1 g/kg, IV, as 20% solution over 20 min every 12–24 hr) has been used to reduce cerebral edema. Anticonvulsants (phenobarbital 2–10 mg/kg, IV, bid; diazepam 0.1–0.4 mg/kg, IV, as needed; midazolam 0.04–0.1 mg/kg, IV, as needed or 0.02–0.06 mg/kg/hr constant-rate infusion) are implemented to treat seizures that can otherwise increase cerebral oxygen consumption and contribute to ongoing injury. Self-trauma during seizures should be limited by providing a protected or padded environment. Trauma to the eye and corneal ulceration is particularly common; the eyes should therefore be monitored closely and treatment implemented if necessary. In recumbent foals, ophthalmic lubricants may be used to reduce the incidence of corneal injury.
Magnesium sulfate supplementation administered as a constant-rate infusion (0.05 mg/kg/hr, IV, loading dose, then 0.025 mg/kg/hr maintenance) has been suggested to block the release of glutamate, whereas antioxidants such as vitamins E (5,000 IU/day, PO) and C (100 mg/kg/day, IV or PO) can be administered along with thiamine (10 mg/kg slowly IV or SC every 12–24 hr) to support cellular metabolism. DMSO 10% solution (0.5 g/kg, IV) has been used as a free radical scavenger. Allopurinol (44 mg/kg, PO, within the first 4 hr), a xanthine oxidase inhibitor, can also be administered to decrease free radicals, whereas pentoxifylline (10 mg/kg, PO, bid) may inhibit TNF-α production in foals with NE.
Most foals with NE will benefit from intranasal administration of humidified oxygen (3–5 L/min), whereas mechanical ventilation may be required in cases of severe respiratory depression. Doxapram (0.02–0.05 mg/kg/hr constant-rate infusion) and caffeine (10 mg/kg, PO or per rectum loading dose, then 2.5 mg/kg as needed) may be used as a central respiratory stimulant. Availability of hyperbaric oxygen therapy is limited, but it has also been used to treat NE in foals. Foals with NE appear to be predisposed to sepsis. Whether this is due to an underlying infectious process, impaired immune function, or increased exposure to pathogens (ie, indiscriminant nursing behavior) is unclear. In addition, foals neurologically abnormal at birth often fail to nurse and commonly have failure of passive transfer of immunity (see Humoral Immunodeficiencies). For these reasons, broad-spectrum antimicrobials, plasma transfusion, and anti-inflammatory management are commonly indicated.
Most foals with NE have a good to very good prognosis. In uncomplicated cases, the reported survival rate is 70%–75%, with complete recovery in most cases. Sepsis and related complications adversely affect the prognosis. Foals that remain comatose or difficult to arouse, show no improvement in neurologic function during the first 5 days of life, or demonstrate severe, recurrent seizures have a guarded to poor prognosis.