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Table 593-15
PATHOPHYSIOLOGY
The immature brain has many differences from the mature brain
that
render it more excitable and more likely to develop seizures.
Based predominantly on animal studies, these are delay in Na+, K+adenosine triphosphatase maturation and increased NMDA and
-amino-3hydroxy-5-methylisoxazole-4-propionate
(AMPA)
receptor density. In addition, the specific types of these receptors
that are increased are those that are permeable to calcium (GLUR2
AMPA receptors). This contributes to increased excitability and to the
long-term consequences associated with seizures, particularly those
resulting from perinatal hypoxia. Medications that block AMPA
receptors, such as topiramate, may thus prove useful in this clinical
setup.
Another difference is delay in the development of inhibitory
GAB- Aergic transmission. In fact, GABA in the immature brain
has an excitatory function as the chloride gradient is reversed
relative to the mature brain, with higher concentrations of chloride
being present intracellularly than extracellularly. Thus, opening of the
chloride chan- nels in the immature brain results in depolarizing the
cell and not in hyperpolarizing it. This phenomenon appears to be
more prominent in male neonates, perhaps explaining their greater
predisposition to
seizures. The reason for this is that the Cl transporter, NKCC1, is
predominantly expressed in the neonatal period, leading to transport
of Cl into the cell at rest, and then to cellular depolarization upon
activation of GABAA receptors and opening of Cl channels with
chlo- ride efflux. This is important for neuronal development but
renders the neonatal brain hyperexcitable. With maturation,
expression of NCCK1 decreases and KCC2 increases. KCC2
transports Cl out of the cell, resulting in reduction of intracellular
chloride concentration so that when GABAA receptors are activated,
Subtle Seizures
Clonic Seizures
Tonic Seizures
Spasms
Spasms are sudden generalized jerks lasting 1-2 sec that are distinguished from generalized tonic spells by their shorter duration and
by
CLASSIFICATION
CHARACTERIZATION
Focal clonic
Focal tonic
Generalized tonic
Myoclonic
Random, single, rapid contractions of muscle groups of the limbs, face, or trunk
Typically not repetitive or may recur at a slow rate
May be generalized, focal, or fragmentary
May be provoked by stimulation
Presumed pathophysiology: may be epileptic or nonepileptic
Spasms
Motor automatisms
Ocular signs
Random and roving eye movements or nystagmus (distinct from tonic eye deviation)
May be provoked or intensified by tactile stimulation
Presumed pathophysiology: nonepileptic
Oral-buccal-lingual movements
Progression movements
From Mizrahi EM, Kellaway P. Diagnosis and management of neonatal seizures. Philadelphia, 1998, Lippincott-Raven. Tab 4, p. 21.
the fact that spasms are usually associated with a single, very brief,
generalized discharge.
Myoclonic Seizures
Seizures vs Jitteriness
ETIOLOGY
HypoxicIschemic Encephalopathy
Vascular Events
Table 593-17
AGES1-4DAYS
Hypoxicischemic encephalopathy
Drug withdrawal, maternal drug use of narcotic or barbiturates
Drug toxicity: lidocaine, penicillin
Intraventricular hemorrhage
Acute metabolic disorders
Hypocalcemia
Sepsis
Maternal hyperthyroidism, or hypoparathyroidism
Hypoglycemia
Perinatal insults, prematurity, small for gestational age
Maternal diabetes
Hyperinsulinemic hypoglycemia
Hypomagnesemia
Hyponatremia or hypernatremia
Iatrogenic or inappropriate antidiuretic hormone secretion
Inborn errors of metabolism
Galactosemia
Hyperglycinemia
cycUleredaisorders
Pyridoxine deficiency and pyridoxal-5-phosphate deficiency (must
be considered at any age)
AGES4-14DAYS
Infection
Meningitis (bacterial)
Encephalitis (enteroviral, herpes simplex)
Metabolic disorders
Hypocalcemia
miDlkiefot,rmula
Hypoglycemia, persistent
Inherited disorders of metabolism
Galactosemia
Fructosemia
senLesiuticvii
ntye
Hyperinsulinemic hypoglycemia, hyperinsulinism,
hyperammonemia syndrome
pitAunittaerryiohrypoplasia, pancreatic islet cell tumor
Beckwith syndrome
Drug withdrawal, maternal drug use of narcotics or barbiturates
Benign neonatal convulsions, familial and nonfamilial
Kernicterus, hyperbilirubinemia
Developmental delay, epilepsy, neonatal diabetes syndrome
AGES2-8WK Infection
simHpelrepxeos r enteroviral
encephalitis
Bacterial meningitis
Head injury
Subdural hematoma
abCusheild
Inherited disorders of metabolism
Aminoacidurias
cycUleredaefects
aciOdrugriaansic
Neonatal adrenoleukodystrophy
Malformations of cortical development
Lissencephaly
coFrtoiccaall dysplasia
Tuberous sclerosis
Sturge-Weber syndrome
Intracranial Infections
Metabolic Disturbances
Drug Withdrawal
DIAGNOSIS
PROGNOSIS
TREATMENT
Lorazepam
Diazepam
Diazepam can be used as an alternative initial drug. It is highly lipophilic, so it distributes very rapidly into the brain and then is cleared
very quickly out, carrying the risk of recurrence of seizures. Like
other intravenous benzodiazepines, it carries a risk of apnea and
hypoten- sion, particularly if the patient is also on a barbiturate, so
patients need to be observed for 3-8 hr after administration. The
usual dose is
0g/.1k-g0I.3Vmover 3-5
min, given every 15-30 min to a
maximum total dose of 2 mg. However, because of the respiratory
and blood pressure limitations and because the intravenous
preparation contains sodium benzoate and benzoic acid, it is
currently not recommended as a first-line agent.
Midazolam
Phenobarbital
For ongoing seizures, if a total loading dose of 40 mg/kg of phenobarbital was not effective, then a loading dose of 15-20 mg/kg of
phenytoin can be administered intravenously. The rate at which the
dose should be given must not exceed 0.5-1.0 mg/kg/min so as to
prevent cardiac problems, and the medication needs to be avoided in
patients with significant heart disease. Heart rate should be
monitored while administrating the drug. It is not possible to mix
phenytoin or fosphenytoin with dextrose solutions. Owing to its
reduced solubility, potentially severe local cutaneous reactions,
interaction with other drugs, and possible cardiac toxicity,
intravenous phenytoin is not widely used.
Fosphenytoin, which is a phosphate ester prodrug, is preferable. It
is highly soluble in water, and can be administered very safely
intrave- nously and intramuscularly, without causing injury to
tissues. Fosphe- nytoin is administered in phenytoin equivalents
(PE). The usual loading dose of fosphenytoin is 15-20 PE/kg
administered over 30 min. Maintenance doses of 4-8 PE/kg/day can
be given. As is the case for phenobarbital, free levels of the drug
Duration of Therapy
is
available
at
Expert
593.8ESptialetp
usticus
Mohamad A. Mikati and Abeer J. Hani
Status epilepticus is a medical emergency that should be anticipated
in any patient who presents with an acute seizure. It is defined as
con- tinuous seizure activity or recurrent seizure activity without
regaining of consciousness lasting for more than 5 min as part of an
operational definition put forth within the past few years. In the
past, the cutoff time was 30 min, but this has been reduced to
emphasize the risks involved with the longer durations. The ILAE
defines status epilepticus as a seizure which shows no clinical signs
of arresting after a duration encompassing the great majority of
seizures of that type in most patients or recurrent seizures without
resumption of baseline central nervous system function interictally.
The measures used to treat status epilepticus have to be started in
any patient with acute seizures that do not stop within a few minutes.
The most common type is convulsive status epilepticus (generalized
tonic, clonic, or tonicclonic), but other types do occur, including
nonconvulsive status (complex partial, absence), myoclonic status,
epilepsia partialis continua, and neonatal status epilepticus. The
incidence of status epilepticus ranges between
10 and 60 per 100,000 population in various studies. Status
epilepticus is most common in children younger than 5 yr of age,
with an inci- dence in this age group of >100 per 100,000 children.
Approximately 30% of patients presenting with status epilepticus
are having their first seizure, and approximately 40% of these later
develop epilepsy. Febrile status epilepticus is the most common type
of status epilepticus in children. In the 1950s and 1960s, mortality
rates of
6-18% were reported after status epilepticus; currently, with the
recog- nition of status epilepticus as a medical emergency, a lower
mortality rate of 4-5% is observed, most of it secondary to the
underlying etiol- ogy rather than to the seizures. Status epilepticus
carries an approxi- mately 14% risk of new neurologic deficits,
most of this (12.5%) secondary to the underlying pathology.
ETIOLOGY
MECHANISMS
Abend NS, Wusthoff CJ: Neonatal seizures and status epilepticus, J Clin
Neurophysiol 29(5):441448, 2012.
Chapman KE, Raol YH, Brooks-Kayal A: Neonatal seizures: controversies
and challenges in translating new therapies from the lab to the isolette,
Eur J Neurosci 35(12):18571865, 2012.
Gillam-Krakauer M, Carter BS: Neonatal hypoxia and seizures, Pediatr Rev
33(9):387396, 2012.
Lawrence R, Mathur A, Tich SNT, et al: A pilot study of continuous limitedchannel aEEG in term infants with encephalopathy, J Pediatr 154:835
841,
2009.