Download Review of Neonatal Seizure Management

MEDICINE—FOAL
Review of Neonatal Seizure Management
Peter R. Morresey, BVSc, MACVSc, Diplomate ACT, ACVIM (Large Animal)
Management of seizure activity in the neonatal foal presents a number of challenges. Control of
neurological dysfunction and prevention of secondary physical injury is necessary in the first instance. Diagnosis of any underlying medical conditions must occur. Wide-ranging knowledge of the
underlying cerebral pathology is essential when formulating a treatment plan. The relatively
limited knowledge of and small number of available drugs further complicates both short- and
long-term management of seizure activity; however, clinical success is possible with a comprehensive
approach to overall patient management. Author’s address: Rood and Riddle Equine Hospital, PO
Box 12070, Lexington, Kentucky 40580; e-mail: [email protected] © 2009 AAEP.
1.
Introduction
Seizure activity in the neonatal foal can result from
cerebral trauma, central nervous system inflammation or infection, compressive intracranial lesions,
cerebral edema, congenital epilepsy, or electrolyte
disturbances secondary to systemic illness. Because the cause of the seizure activity may not
readily be apparent, the first goal of therapy is to
control seizure activity and prevent secondary physical injury. Once seizure activity is stabilized, determination of any underlying medical conditions
can proceed with an assessment of the systemic
health and metabolic state of the neonate.
2.
Seizure Recognition
Seizure activity is an indication of forebrain neurological dysfunction as the result of abnormal
electrical activity within the brain. Involuntary,
spontaneous muscle contractions are accompanied
by varying degrees of loss of consciousness. Seizures may be further divided into focal or partial
(initially involving a small part of the brain with
limited manifestations) or generalized (widespread
involvement of the brain with recumbency and loss
NOTES
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of consciousness possible). Partial seizures do not
necessarily progress into general seizures. Seizures of cerebral origin often remain predictable and
non-progressive with respect to their severity and
duration. However, when caused by an underlying
systemic problem, seizure activity often worsens
with any deterioration in the precipitating disease
process.
Three phases of a seizure episode are recognized.
The pre-ictal period may involve depression, abnormal activity, and star-gazing. The ictal period
(overt seizure) encompasses the recognized manifestations of seizure activity: paroxysmal muscle contraction and altered consciousness. The post-ictal
phase is one of depression and possible transient
loss of neurological function (e.g., central blindness).
Diagnosis of seizure activity in the neonatal foal is
challenging but an essential component of successful
management of the condition. Only subtle signs
suggestive of seizure activity may be displayed.
These include any or all of the following: abnormal
eye movements, tremors, excessive stretching when
recumbent, excessive extensor tone, hyperaesthesia
to touch and attempts at physical manipulation, and
MEDICINE—FOAL
itating a self-sustaining cycle of cell damage and
aberrant electrical activity.3
4. Conditions Associated With Seizure or Seizure-Like
Activity
Seizure disorders of the foal can result from compromise of the dam or placenta during the fetal period
or from disease processes encountered by the neonatal foal including hypoxic insult and sepsis. Medical management of the foal at risk from the onset of
seizure activity should ensure adequate ventilation
(avoid hypercapnia that leads to central depression),
prevention of hypotension, avoidance of hypoglycemia/hyperglycemia, and control of any detected
seizure activity.4 Underlying medical conditions
(infectious, inflammatory, developmental, congenital) must be managed, and any lesions amenable to
surgical correction addressed concurrently with seizure control.
Fig. 1. Overt seizure activity may not be noted; unexplained
trauma may therefore be the only indication of neurological
dysfunction.
apneustic breathing.1 Overt seizure activity is easier for the clinician to detect: manifestations including rapid nystagmus, paddling, focal, or generalized
muscle fasciculations, hyperextension of the limbs
and neck, excessive mouth movements (chewing
gum fits), and occasionally abnormal vocalization.
Further complicating diagnosis are unobserved
episodes of seizure activity. The presence of unexplained physical trauma, for example, nasolabial
and gingival excoriation, may be the only evidence of
neurological dysfunction (Fig. 1).
3.
Pathogenesis of Seizure Activity
Disruption of neural tissue, whether as a result of
infection, ischemia, or trauma, involves many processes including vascular and cellular disruption, free
radical production, breakdown of cell membrane lipids, and the release of inflammatory mediators.
Apoptosis of neurons occurs as a result of aberrant Ca
intakes and excitotoxic neurotransmitter release.
Loss of astrocyte functions during cerebral ischemia
also affects neuronal cell viability.2 Astrocytes provide structural, nutritional and metabolic support to
neurons. Furthermore, synaptic activity and glutamate uptake are regulated, free radicals are scavenged, and local inflammatory mediator production
is modulated.
Excitatory amino acids (including glutamate, aspartate) have been shown to be the final common
pathway in many neurologic disorders. Activation
of glutamate receptors allows an excessive influx of
calcium into neurons through ionic channels. Neuronal swelling results, with the subsequent membrane damage and cell death releasing further
glutamate from intracellular storage vesicles, facil-
Hypoxic Ischemic Encephalopathy and Perinatal Asphyxia
Syndrome
The result of cerebral hypoxic or ischemia insult to
the neonate, hypoxic ischemic encephalopathy and
perinatal asphyxia syndrome (HIE/PAS) is arguably
the most common seizure precipitating syndrome
faced by the equine clinician. Excitatory amino acids, calcium ions, free radicals, NO, pro-inflammatory cytokines, and products of lipid peroxidation
are all thought to contribute to the HIE/PAS syndrome. Compared with the adult, the immature
neonatal brain seems to have an increased susceptibility to excitotoxic and free radical damage, with
an increased propensity for apoptotic cell death.5,6
The diagnosis of HIE/PAS is dependent on a compatible history and clinical examination findings
while ruling out other conditions.1 Confounding diagnosis, sepsis and major organ dysfunction may
occur concurrently. Depressed pulmonary function
(decreased ventilation) promotes retention of CO2,
leading to central depression and abnormal acidbase balance. Renal compromise (ischemia) can result in electrolyte (sodium) and fluid balance
derangements. With the loss of normal gastrointestinal motility and integrity, intestinal bacterial
overgrowth can lead to diarrhea and sepsis.
In the neonatal foal, many recommendations for
the treatment of neurological dysfunction resulting
from HIE/PAS are empirical and extrapolated from
other species.7
Trauma
Trauma was the cause of 22% of central nervous
system disorders in one equine study.8 In addition
to episodes of seizure activity, trauma can lead to
abnormal mentation, gait, and posture. Mild cases
often present with subtle neurological deficits,
whereas in others, spinal reflexes may be diminished. Severe cases can present in recumbency.
With any case of overt trauma, there may be direct injury of the neural tissue itself. Onset of neuAAEP PROCEEDINGS Ⲑ Vol. 55 Ⲑ 2009
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rological signs may be delayed because the
pathophysiology of central nervous system (CNS)
injury is complex and progressive. Ongoing hemorrhage or swelling of neural tissue within the bony
confinement of the calvarium, sudden displacement
of bony fragments, and disturbances of blood pressure and perfusion exacerbate the initial cerebral
insult.
Metabolic Derangement
Glucose levels are frequently abnormal in the
compromised neonate, with both hypoglycemia
and hyperglycemia potentially having effects on
neurological function. Additionally, although other
electrolyte disturbances occur, derangements of sodium and calcium are the most relevant with respect
to neonatal seizure disorders.
Hypoglycemia
Considering human neonatal glucose concentrations
in isolation, insufficient information is currently available to determine a minimum value of glucose occurring during the neonatal period (for any one time or
any period of time) below which irreparable hypoglycemic injury to the central nervous system ensues.9
However, hypoxia, neonatal seizure, and pathological
jaundice have been shown to exacerbate hypoglycemic
brain injuries in cases of severe and prolonged neonatal hypoglycemia.10 Hypoglycemia itself has been
shown to be a risk factor for perinatal brain injury in
term infants who require resuscitation and those that
have suffered severe fetal acidemia.11
In a recent review, foals with lower mean blood
glucose concentrations at admission or high maximum and low minimum blood glucose concentrations within the first 24 h of hospitalization were
less likely to survive to discharge. This was
thought not to be a result of hypoglycemia causing
cerebral dysfunction, but a result of the association
of hypoglycemia with sepsis, bacteremia, and the
systemic inflammatory response syndrome (SIRS).12
The effect of hypoglycemia on seizure activity is
therefore not proven.
Hyponatremia and Hypernatremia
The brain has limited ability to adapt to alterations
in serum osmolarity. It is the rapidity with which
the sodium disturbance develops that determines if
hyponatremia and hypernatremia cause overt
neurological deficits. Acute hyponatremia results in cerebral edema caused by the osmotic
draw of the hypertonic cell interior. Seizure activity, blindness, and depression can result because of compression of the brain against the bony
calvarium. Chronic hyponatremia is less likely
to produce neurologic symptoms because osmotic
equilibrium has time to occur. The rapid correction of hyponatremia is likely to cause neurological signs because of increased plasma osmolality,
causing cell shrinkage by the osmotic draw of water from cells.13
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By the same osmotic draw, acute hypernatremia
may cause shrinkage of brain parenchyma. As
with other causes of cerebral injury, neurons produce idiogenic osmoles (osmotically active metabolic
byproducts) in an attempt to counter the extracellular hyperosmolality by maintaining intracellular osmotic draw. Unfortunately, these compounds
promote intracellular edema during correction of hypernatremia if the rate of correction is not carefully
monitored. Parenchymal hemorrhages may occur
through tearing of bridging veins, with these sometimes progressing to subdural hematomas in severe
cases causing compression of the brain.
Hypocalcemia
Seizure activity (focal or generalized) is the most
common central neurologic manifestation of hypocalcemia. Agitation, confusion, and depression
may also occur. Tetany is the most frequently recognized peripheral nervous system symptom of
hypocalcemia. When the ionized calcium concentration reaches a low enough level, the nerve cell
membrane electrical potential reaches a level allowing spontaneous discharge, leading to clusters of
irregular, repetitive action potentials. In a case series reported by Beyer et al.,14 five foals with low
measured and corrected total serum calcium showed
neuromuscular signs including recumbency and seizure-like activity. Corrected total serum calcium
levels were ⬍7.5 mg/dl in all the affected foals.
Ionized calcium levels for those foals measured were
below the normal reference range for the consulting
laboratory (⬍1.58 mM).
Hepatic Compromise
Hepatic dysfunction leads to the systemic accumulation of ␥ amino butyric acid (GABA) and other
undesirable metabolic products such as ammonia.
Branched chain amino acids decrease and aromatic
amino acids increase. Centrally, these metabolic
changes alter the ratio of GABA (inhibitory) and
L-glutamate (excitatory) amino acids in favor of seizure propagation. Endogenous benzodiazepinelike compound concentration is increased, leading to
centrally mediated depression.
Hyperbilirubinemia
Bilirubin has many toxic intracellular effects. Oxidative phosphorylation is curtailed, membrane
structure and function are changed, neurotransmitter metabolism is inhibited, and cell regulatory
proteins are altered in structure and function.
Prematurity/immaturity, hemolysis, asphyxia, acidosis, sepsis, and increased bilirubin itself may increase bilirubin absorption by nervous tissue.15
Most important to the neonatal foal is hemolysis,
whether by sepsis (intravascular) or neonatal isoerythrolysis (extravascular). Kernicterus, a condition where bilirubin encephalopathy occurs, has
been reported in the foal.16 Degeneration and necrosis of cerebral neurons occurs.
MEDICINE—FOAL
Infectious Agents
Pathogens, whether viral or bacterial, have the ability to cause substantial CNS inflammation by their
own actions or by the initiation of an excitotoxic
neurotransmitter cascade. Meningitis and encephalomyelitis has been extensively reviewed.17 The
neonatal foal is susceptible to meningitis resulting
from systemic bacteremia caused by an increased
permeability of the blood– brain barrier.
Developmental or Congenital Cerebral Abnormalities
neonatal neurological disease. With radiography,
congenital malformations, disruption of bony structures, and deviation of neural tissue by trauma can
be visualized. Both plain and contrast studies are
possible. MRI is invaluable in the assessment of
soft tissue, foci of infection, or vascular disruption.
6.
Once a diagnosis of a seizure disorder has been
made, the treatment plan should seek to address the
following clinical goals:
In one retrospective study, hydrocephalus occurred
in 3% of foals that died or were euthanized.18 Hydrocephalus may be clinically silent or
precipitate seizure activity.
●
●
●
Congenital Epilepsy
This condition is reported in some breeds. A recent
review of Egyptian Arabians19 showed seizure activity
itself to be self-limiting with age. Complications in
affected foals included head trauma and pneumonia.
5.
Treatment Goals
●
●
Manage seizure episodes and any concurrent
neurologic dysfunction
Restore cerebral perfusion and oxygenation if
compromised
Control cerebral edema and inflammation if
present
Provide metabolic requirements of the debilitated patient
Address concurrent physical injuries and medical conditions if present
Aids in the Diagnosis of Seizure Activity
Complete Blood Count and Serum Chemistry
Assessment of the systemic health of any foal displaying seizure activity is essential. A complete blood
count (CBC) aids in the diagnosis of systemic infection
that may have spread to the CNS. Ongoing cerebral
hypoxia as a result of anemia will be suggested.
Serum chemistry evaluation assesses major organ system function, chiefly liver (removal of blood borne toxins) and kidney (assessment of electrolyte
homeostasis). Immunoglobulin G (IgG) levels are a
direct measure of the transfer of passive immunity
from the mare, critical for immune defenses in the
otherwise hypogammaglobulinemic neonatal foal.
A number of studies have shown a relationship between the IgG concentration and the occurrence of
neonatal disease including sepsis.20,21 Sepsis is a
major differential diagnosis in the neonate affected by
neurological disease and can itself contribute to neurological dysfunction.22 Blood gas evaluation assesses pulmonary gas exchange and enables
determination of the acid-base status of the foal.
Cerebrospinal Fluid Analysis
In suspected cases of meningitis, cytology and microbiological culture of the cerebrospinal fluid (CSF)
is useful for diagnosis, antimicrobial selection, and
prognosis. Total protein concentration, nucleated
cell count, and red blood cell (RBC) count should be
routinely performed. Where increased intracranial
pressure is suspected, this procedure should be
avoided because aspiration from the atlantal-occipital space can lead to herniation of the brain through
the foramen magnum.
Radiography and Magnetic Resonance Imaging
Both radiography23 and magnetic resonance imaging (MRI)24 have been reported in the diagnosis of
With respect to the precipitation of seizure activity within the brain, consideration of a number of
therapeutic targets is necessary including glutamate accumulation, aberrant calcium fluxes, free
radical formation, lipid peroxidation, and generation of arachidonic acid metabolites.3,25,26
Blockade of the N-methyl-D-aspartate (NMDA) receptor mediating excitotoxic neuronal damage has
been useful in both in vivo and in vitro models of
cerebral ischemia and trauma.27,28 Cell death results
from excessive activation of the NMDA glutamate receptors, allowing excessive Ca influx through a receptor-associated ion channel. Experimental glutamate
toxicity can be decreased by NMDA antagonists administered after the initial insult.3 In addition to
NMDA receptor activation, intracellular Ca accumulation may also be caused by calcium-mediated neuronal depolarization and loss of cell membrane
integrity.27 Glutamate excitotoxicity is a cause, result, and potentiator of calcium-induced cellular
breakdown; therefore, glutamate control through
NMDA receptor blockade provides a rational therapeutic target to ameliorate neuronal damage.
7.
Readily Available Drugs Useful for Seizure Control
Although many seizure controlling medications are
available in human medicine, veterinary access to
most is limited. This review will be limited to those
drugs readily accessible to the practicing equine
veterinarian.
Benzodiazepines
Drugs of this class are widely used for their anxiolytic, sedative, narcotic, anticonvulsant, and muscle
relaxant effects, with differences between members
resulting from varying absorption and metabolism.29 The benzodiazepines are important in the
management of seizure disorders associated with
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fever and hypoxic insult and are the first choice
therapy for status epilepticus.30 Benzodiazepines
show high efficacy rates, a rapid onset of action, and
have minimal toxicity to the patient.
Diazepam
Diazepam is best used in the emergency control of
seizures.30 Chronic oral administration of diazepam is unsuitable for long-term seizure management because efficacy is doubtful. Diazepam has a
very short half-life, induces hepatic enzymes, and
may create tolerance rendering diazepam ineffective
for controlling seizures during emergencies.31
The use of diazepam in the control of equine neonatal seizures is widely reported. Rapid onset of
short-term control of acute seizures is achieved with
minimal depression to the foal. Recurrent seizure
activity is often managed with repeated administration of diazepam as required; however, phenobarbital administration to effect is recommended in cases
where two or more seizures occur over a short
period.
Midazolam
Midazolam is the only available water-soluble benzodiazepine.30 Midazolam is fast acting, rapidly
penetrates the blood– brain barrier, and has a relatively short duration of action. Use in the treatment of refractory human neonatal seizures has
been reported, with more than one third of all human neonatal seizures being refractory to high dose
phenobarbital.32,33
The use of midazolam in the control of neonatal
foal seizures has been reported with administration
through both the IV and IM route. Initial control of
a seizure episode can be readily achieved by bolus
intravenous administration, with ongoing seizure
control maintained with an intravenous constant
rate infusion.34 Side effects include respiratory depression and hypotension.
Barbiturates
Phenobarbital
Phenobarbital is used in the management of acute
seizure episodes not responding to shorter-acting
agents (by IV infusion) and recurrent seizure activity (constant rate infusion, chronic oral dosing).
Phenobarbital can be considered a mainstay of seizure control. Onset of action is rapid, with the
threshold of neurons to seizure activity initiation
and propagation raised. Depression may result on
initial administration of the drug; however, in
chronic dosage situations, this is overcome by the
induction of hepatic enzyme metabolism. Serum
levels therefore require monitoring to ensure the
foal remains within the therapeutic range during
long-term maintenance therapy.35,36
Pentobarbital
Pentobarbital is an intravenous anesthetic barbiturate that depresses neuronal excitability by enhanc26
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ing GABA-coupled responses. Pentobarbital is the
first metabolite of thiopental. In comparison to
phenobarbital, pentobarbital penetrates the brain
faster, allowing more rapid seizure control, and has
a shorter half-life, allowing quicker recovery. Sodium pentobarbital is generally reserved for the
treatment of uncontrollable status epilepticus.
Accumulation may occur with prolonged use because of lipid solubility. Pentobarbital use is associated with respiratory depression, myocardial
depression, hypotension, and low cardiac output.33
Phenytoin
The use of phenytoin in the control of neonatal seizures has been reported.33 However, little is
known about the pharmacokinetics of phenytoin in
the equine neonate, with erratic plasma concentrations reported. Considerable depression of some
foals has also occurred.
Cyclohexylamines
Ketamine
The use of ketamine in the management of human
refractory status epilepticus has been reported, although this drug has traditionally been avoided in
patients with neurological injury.33 Ketamine has
been associated with improved cerebral perfusion,
likely by increasing blood pressure because of its
sympathomimetic properties.37 This is in contrast
with most medications used for refractory status
epilepticus that reduce blood pressure.
NMDA receptor antagonism, in addition to being
the most important mechanism causing the analgesic
effects of ketamine, is also thought responsible for its
purported neuroprotective action.38 Blockade of excitatory transmission at the NMDA receptor provides
an approach to the initial treatment of cerebral ischemia.39 Blockage of excessive NMDA receptor allows
regulation of intracellular calcium levels and attenuated induction of NO, reducing neuronal degeneration
and death. Cellular morphology was preserved,
cellular energy status and ATP production were
protected, and reduced cell swelling was noted
subsequent to anoxia-hypoxia or excitatory neurotransmitter injury.40
Ketamine is useful for the short-term management of seizure activity, being administered as a
constant rate infusion after control of a seizure episode. In the author’s experience, this technique is
most applicable to those foals maintained in recumbency because of concurrent debilitating medical
conditions. The foal is first induced to a light plane
of narcosis (diazepam followed by ketamine) and
then the infusion is started. Foals vary in their
response, some progressing to a state of light but
rousable sedation, with others maintaining an appropriate level of awareness and responsiveness to
stimulation.
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Other
Potassium Bromide
Potassium bromide (KBr) has been used since the
19th century as a human anticonvulsant and sedative. After their first use in 1853, bromides (potassium, sodium, and ammonium) were the mainstay of
epilepsy control until replacement by phenobarbital
beginning in 1912.41
It is currently widely used in the management of
refractory canine epilepsy. Use in horses has
been reported chiefly in adults; however, control in
idiopathic epilepsy of foals has been reported.19
Pharmacokinetics in adult horses have been reviewed.42 The author has also found KBr useful
adjunctively in the control of neonatal seizures
incompletely controlled by other agents.
Propofol
Propofol is a short-acting intravenous hypnotic anesthetic agent useful for control of refractory status
epilepticus. Propofol may have anticonvulsant activity, because it is GABA-mimetic, stabilizing
GABA inhibitory neurotransmitter sites. Use in
cases of prolonged seizure activity or status epilepticus has been reported in humans.43 Use in the
neonatal foal for refractory seizure activity is possible with the favorable depressant characteristics of
the drug; however, financial considerations may preclude widespread use.
Magnesium
The magnesium ion acts as an antagonist of cell
membrane calcium channels in many tissues.44
It also acts as a voltage-dependent blocker of the
NMDA channel, suggesting beneficial effects in the
prevention of neuronal cell death and seizure propagation, although this is reduced after neural injury.45 Cell membrane integrity and permeability
have also shown to be improved by Mg administration, as has functioning of the Na1/K1 ATPase membrane pump, which enables a reduction in cell
edema.
Gabapentin
Gabapentin is a structural analog of GABA, although the exact mode of action is unknown. It has
been reportedly used for neuropathic pain in the
horse, and pharmacokinetics have been recently reviewed.46,47 Use for seizure control in the horse
has not been widely reported. Further study is required before gabapentin can be recommended for
seizure control.
8.
Supportive Care of Seizure Patients
Treatment of existing trauma, prevention of further
injury, strict attention to fluid balance, control of
inflammation, and provision of the metabolic requirements of the patient are as integral to successful patient management as control of seizure
activity itself.
Wounds, contusions, and decubital ulceration
should be aggressively locally managed with topical
treatments and dressings. Concurrent systemic
antimicrobials to counter bacterial dissemination in
the compromised neonate will be required.
Appropriate leg wraps will aid in the prevention of
distal limb edema and secondary limb injury.
Head protection “bumpers” minimize the occurrence
of secondary neurological injury from repeated cranial trauma in the recumbent or seizing foal. If
recumbent, the foal should be provided a supportive
bed and a means to cleanly eliminate body waste.
Slight elevation of the head can prevent dependent
edema affecting the brain. Corneal ulceration secondary to abrasion or exposure keratitis can be prevented by regular application of ophthalmic
lubricants.
Drug options for sedation of the seizing patient to
minimize self-trauma are limited; however, the ␣2
adrenergic agonists and benzodiazepines possess favorable qualities of sedation and muscle relaxation.
Contraindicated drugs include butorphanol (because of a potential increase in CSF pressure) and
acepromazine (lowers the seizure threshold).
Fluid Therapy
In addition to meeting the metabolic needs of the patient, appropriate fluid therapy is essential to ensure
adequate cerebral perfusion, which may have been
compromised by the cerebral insult that precipitated
the seizure activity. Restoration of cerebral perfusion
allows the re-establishment of autoregulation, the process whereby the brain controls its own perfusion rate
and pressure despite fluctuations in arterial blood delivery. The loss of autoregulation has been reported
after cerebral ischemia and reperfusion or traumatic
brain injury.48
An appropriate fluid balance maintains cerebral
perfusion and oxygenation while avoiding increased
intracranial pressure. Maintenance of appropriate
oncotic pressure with sedation to decrease cerebral
energy metabolism is also beneficial.49
Systemic dehydration has not been shown to decrease existing cerebral edema, and a negative fluid
balance has been proven to be detrimental to overall
patient outcome.50 Overhydration must also be
avoided because this potentiates CNS edema after
cranial trauma and exacerbates pulmonary edema
in recumbent patients.
Although used widely clinically, hypo-osmolar solutions such as 5% dextrose in water increase intracranial pressure caused by decreased serum sodium and
increased brain water.51 Iso-osmolar, polyionic fluids
are therefore indicated in the chronic management of
neurologically compromised patients once concerns of
cerebral edema have been overcome.
Control of Cerebral Edema
Edema of the brain causes compression against its
bony confinement and further trauma as well as a
decrease in perfusion and oxygenation. Edema
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may be caused by disruption of the blood– brain barrier, cellular disruption causing intracellular water
collection, and the result of osmotic imbalances between blood and tissue.52
The mainstay of edema control has traditionally
been the use of diuretics and hyperosmolar agents.
Diuretics such as furosemide have little effect on
cerebral edema because establishing an osmotic
gradient across the blood– brain barrier does not
require systemic dehydration.53 Hyperosmolar (osmotic) agents are central to the control of increased
intracranial pressure, although firm guidelines for
their use do not exist.
Mannitol
Mannitol is a polyol (sugar alcohol) used as an osmotic diuretic. As a hyperosmolar agent, mannitol
establishes an osmotic gradient across the blood–
brain barrier and improves overall blood delivery to
the brain while decreasing intracranial pressure.54
Additionally, in common with all hyperosmolar
agents, mannitol causes plasma volume expansion
with a resultant decrease in blood hematocrit and
therefore viscosity, and decreases cerebral blood
volume.55
Hypertonic Saline
An intact blood– brain barrier is less permeable to
saline than to mannitol; hypertonic saline is therefore a more effective and long-lasting hyperosmolar
agent able to resolve cases refractory to mannitol
infusion.53 Hypertonic saline solutions decrease
brain water and intracranial pressure while temporarily increasing systolic blood pressure and cardiac
output.51 The use of hypertonic saline for increased intracranial pressure has been shown to
increase survival compared with mannitol use.56
Concentrations used range from 3% to 10%.57
emia.59 Glucocorticoids downregulate cytokinemediated COX-2 expression by monocytes and
astrocytes.60 Glucocorticoids inhibit phospholipase
A2, attenuating release of arachidonic acid from the
cell membrane and inducible NO synthase (iNOS)
expression.61 Upregulation of pro-inflammatory
cytokines by nuclear factor ␬B (NF-␬B) is also
blocked.62
Cyclooxygenase inhibitors, such as the NSAIDs,
should therefore have an additive anti-inflammatory effect if administered concurrently with glucocorticoids. The use of glucocorticoids where
cerebral insult is suspected is controversial; however, utility in cases of acute bacterial meningitis
has been shown.63
Dimethyl Sulfoxide
Recognized as an anti-inflammatory, dimethyl sulfoxide (DMSO) is also credited as a free radical scavenger, antioxidant, diuretic, vasodilator, and Ca
channel blocker. With consideration of the pathophysiology of cerebral insult, DMSO administration
is rational in cases of neural trauma.64 DMSO has
been shown to rapidly reduce raised intracranial
pressure and increases cerebral perfusion without
affecting the systemic blood pressure.65
Loop Diuretics
Diuretics such as furosemide will lead to global dehydration of the foal, which is detrimental to outcome because of the decrease in cerebral perfusion
and oxygenation resulting from hypovolemia.50
Therefore, in the absence of peripheral or pulmonary edema, loop diuretics are not indicated in seizure cases where cerebral edema is suspected.
Antioxidants
Lipid peroxidation is considered a major cause of cell
damage and death after neurological insult. Antioxidants have been shown capable of inhibiting
edema, metabolic derangements, and ischemia of
affected tissue.66
Pretreatment of animals with vitamin E (␣-tocopherol) has been shown beneficial in cases of neurological
trauma, decreasing ischemia and enhancing recovery.
Vitamin E is thought to act as a peroxyl free radical
scavenger. Chronic dosing is necessary because of
slow uptake by the CNS tissue, making it an impractical agent for acute treatment.67
Vitamin C (ascorbic acid) is associated with glutamate release in the brain, suggesting a neuroprotective or neuromodulating effect is possible
therapeutically.68 The synaptic action of dopamine is affected, and the NMDA glutamate receptor is altered, which blocks NMDA-gated channel
function.69
Inflammation
Nutrition
Anti-Inflammatories
Non-steroidal anti-inflammatory drugs (NSAIDs)
attenuate inflammation associated with brain and
spinal cord injury. Arachidonic acid metabolites
promote platelet aggregation and facilitate inflammatory and immune reactions. Experimentally,
cyclooxygenase (COX) inhibitors improve cerebral
blood flow, decrease edema, protect COX-2– expressing neurons, and attenuate microglial activation.58
Glucocorticoids are immunosuppressive and diminish monocyte infiltration after cerebral isch-
Protein and energy malnutrition has been shown to
exacerbate brain injury and worsen functional outcome during periods of global ischemia. This is as a
result of increased oxidative stress and an inflammatory response to ischemia.70 In cases of cerebral
trauma, metabolic requirements have been shown to
be increased above maintenance levels.71 Provision
of adequate nutrition is therefore important in all
cases of cerebral dysfunction regardless of the presence of seizure activity. However, seizure activity
places extreme demands metabolically on the affected
animal, rapidly depleting energy stores.
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Table 1.
Drugs Used in Treatment of Neonatal Seizure Disorders
Indication
Drug
Dose Rate
Comment
IV, IM (high doses). Long-acting.
IV, IM. May exacerbate seizure activity. Shortacting.
IV. Short-acting.
IV. Maintain with 0.1–0.2 mg/kg/h constant rate
infusion.
IV loading dose diluted and administered over
15–30 min. Chronic oral maintenance 4–10 mg/
kg, q 12 h. Long-acting. Therapeutic levels
range 5–30 ␮g/ml.
IV. May induce severe respiratory depression.
Use only when non-responsive to other agents.
IV. Maintain with 1 mg/kg/h constant rate
infusion.
Sedation
Detomidine
Xylazine
0.005–0.04 mg/kg
0.02–1.1 mg/kg
Seizure control
Diazepam
Midazolam
0.05–0.4 mg/kg
0.2-mg/kg bolus
Phenobarbital
5–25 mg/kg
Pentobarbital
3–5 mg/kg
Propofol
2-mg/kg induction
Flunixin
Phenylbutazone
Hypertonic saline
Mannitol
Magnesium sulfate
1.1 mg/kg
2.2–4.4 mg/kg
7 ml/kg
1 mg/kg
0.05 mg/kg
Ketamine
0.02 mg/kg/min
Vitamin E
Vitamin C
Thiamine
Dimethyl sulfoxide
10–20 IU/kg
100 mg/kg
10 mg/kg
1 g/kg
Potassium
bromide
30 mg/kg
Control of inflammation
NSAIDs
Cerebral edema control
NMDA blockade
Miscellaneous
9.
Case Example
A 7-day-old, 45-kg Thoroughbred foal was hospitalized for the recurrence of depression and loss of
suckle reflex. The foal had previously been treated
beginning at 2 days of age for HIE/PAS, with therapies including antimicrobials, anti-inflammatories,
antioxidants (DMSO, vitamin C), and supportive
care until the foal could feed itself. The foal was
considered to have made a complete recovery after 3
days of treatment.
On admission at 7 days of age, the foal was found
to be mildly depressed but in otherwise good condition. Screening blood work did not indicate the
presence of infection, major organ dysfunction, or
metabolic derangement. Treatment consisted of
supportive care, antimicrobial coverage, anti-inflammatories, and antioxidants. The foal rapidly
improved, with a return to normal behavior and
feeding activity within 24 h of admission.
Seizure activity occurred on the third day of hospitalization (10 days of age). Head pressing, tetany, rapid pacing, and dementia were present.
Administration of diazepam (5 mg, IV, twice with a
IV, q 12 h; PO, q 24 h
IV or PO, q 12–24 h
IV as 3% solution
IV as 20% solution
IV over 30 min. Control excitotoxic glutamate
neurotransmitter cascade.
IV constant rate infusion. Induces a varying level
of central depression with beneficial
cardiovascular effects.
PO, q 24 h. Control lipid peroxidation.
IV, q 12 h. Antioxidant.
IV, q 12 h. Metabolic support.
IV, q 12 h as 10% solution. Free radical
scavenger, anti-inflammatory.
PO, q 24 h. Useful adjunct therapy or may be
used as the sole agent for long-term
management. Therapeutic range 1–3 mg/ml
(controversial, adult value extrapolated from
other species).
5-min interval) did not resolve the seizures. Phenobarbital was infused (10 mg/kg over 15 min twice
with a 20-min interval), which also did not arrest
seizure activity. Pentobarbital (3 mg/kg, IV injection) led to a period of narcosis and resolution of the
seizure episode. The foal was immediately placed
on a ketamine constant rate infusion (induced with
0.05 mg/kg diazepam and 1 mg/kg ketamine, IV,
followed by 0.02 mg/kg/min ketamine infusion).
After 24 h, the infusion rate was halved and maintained for a further 12 h. During this time, oral
phenobarbital maintenance therapy at 4 mg/kg
twice daily was instituted. Supportive therapy was
discontinued, with the foal becoming ambulatory,
and suckling activity was restored. Oral potassium
bromide was begun (20 mg/kg three times daily for 2
days, loading dose decreased to 30 mg/kg once daily)
in conjunction with the phenobarbital.
The foal was discharged, and no further incidents
of seizure activity were reported. Serum phenobarbital levels were measured at 4 days and 3 h after
dosage36,72 to allow peak concentrations to be measured (8 ␮g/ml). Phenobarbital and potassium broAAEP PROCEEDINGS Ⲑ Vol. 55 Ⲑ 2009
29
MEDICINE—FOAL
mide were tapered after 1 mo of treatment, being
decreased to half dose for a further 2 wk and then
discontinued. The foal has continued to develop
normally without incident.
The phenobarbital levels measured in this foal are
considered to be below the established therapeutic
range for horses. Assessment of phenobarbital levels should be performed after the establishment of
steady-state concentrations. This occurs after five or
six elimination half-lives, with each half-life being
12 hours long.72 In this case, the adjunctive use of
potassium bromide may allow a lower level of phenobarbital to maintain effective seizure control.
10.
Summary
Control of neonate seizure activity presents diagnostic and therapeutic challenges to the equine clinician. A thorough understanding of the underlying
pathology of neurological dysfunction is required.
Concurrent or precipitating medical conditions must
be managed. Along with management of the seizure activity, re-establishment of appropriate cerebral blood flow, fluid balance, and nutrition is
essential to successful management of these cases.
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