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Neonatal Seizures Carl E. Stafstrom Pediatrics in Review 1995;16;248 DOI: 10.1542/pir.

16-7-248

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pedsinreview.aappublications.org/content/16/7/248

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1995 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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ARTICLE

Neonatal
Carl E. Stafstrom, FOCUS QUESTIONS

Seizures
MD, PhD*
behavior or autonomic function (an example of electroclinical dissociation). Thus, even in a single infant, seizures can arise from more than one focus (multifocal) at different times. Many electrographic seizures may be undetected clinically. Because it is impractical to have continuous EEG monitoring in most neonatal nurseries, clinical guidelines are needed to determine when and how aggressively electrical seizures should be treated. The most easily recognized variety of neonatal seizure is the clonic seizure, which involves rhythmic jerking Types of Neonatal Seizures of one or more parts of the body. Because their brains are immature, Clonic seizures may be focal (involving a single limb, both limbs on one neonates exhibit a somewhat different repertoire of ictal behaviors from side of the body) or multifocal (eg, left arm and right leg jerking together older children and adults. Neonatal seizure manifestations often are sub- or, more commonly, independently in Unlike in seizures of older tle and can change from moment to time). children or adults, there very rarely is moment. Neonatal seizures can be a jacksonian march or slow, sequenclassified into several clinical types, tial spread of ictal activity in neonabased on visual observation (Table 3). Using the technique of simultatal clonic seizures; rather, seizures neous video-EEG recording, it has tend to be migratory, first affecting then the opposite leg, etc. been possible to determine which of one hand, Furthermore, generalized tonic-clonic these clinical seizures are accompanied by electrical discharges on EEG seizures that commonly are seen in (Table 3). Some clinical behaviors older individuals rarely if ever are in neonates because the immathat appear to be seizures do have an seen ture nervous system is unable to proEEG correlate, but many such cliniand sustain this type of seizure cal behaviors are not accompanied by duce abnormal electrical activity. These activity. Consciousness often is preserved in focal neonatal seizures. Foobservations suggest that the various cal and multifocal clonic seizures types of neonatal seizures may have are accompanied by ictal disdifferent pathophysiologic bases, and usually charges (rhythmic spikes) on EEG. In each may require a different theracontrast to older patients, a focal seipeutic approach. zure in a neonate does not necessarFigure 1 shows examples of EEG ily imply focal brain pathology; a recordings from a 19-day-old term generalized metabolic disturbance female who suffered severe perinatal such as hypoglycemia may cause a hypoxia and developed seizures on seizure in a neonate. her first day of life. Figure lA shows focal Myoclonic seizures are charactera seizure originating from the left ized by rapid isolated jerks of the hemisphere (central-parietal area), where there is a build-up of highentire body or can be fragmentary and involve only certain body parts. voltage rhythmic discharges. This Myoclonic seizures usually signify electrographic seizure was accompacentral nervous system innied by rhythmic jerking of the right massive jury such as HIE or major cerebral arm and hand. Eight minutes later malformation. In surviving infants, (Figure lB), another electrographic seizures may evolve into seizure arose independently from the myoclonic spasms, and other grave opposite cerebral hemisphere, but it infantile neurologic sequelae may develop. In was not accompanied by clinically some neonates who have myoclonic observable changes in the infants
Pediatrics in Review Vol. /6 No. 7 Juls 1995

What are the most common causes of seizures in the newborn? 2. How do seizures in the newborn differ from seizures in older children and adults? 3. What clinical features characterize the various types of seizures in the newborn period? 4. What correlations exist between clinical and electroencephalographic phenomena In newborn infants who have seizures? 5. What principles should guide the use or choice of anticonvulsants for neonatal seizures?

1.

higher incidence among sicker preterm infants. Incidence also depends on etiology; as many as 50% of newborns who have severe hypoxic-ischemic encephalopathy (HIE) develop neonatal seizures. Mortality among neonates who have seizures ranges from 15% to 40% and depends largely on the underlying etiology. Despite the high incidence and severity of neonatal seizures, controversy abounds regarding nearly every aspect of their diagnosis, pathophysiology, and management.

Definitions

and

Epidemiology

A seizure is a sudden, paroxysmal discharge of a population of neurons that causes a transient alteration in neurologic function. This alteration may involve abnormal motor activity, sensory symptoms, a change in the level of alertness, alteration in autonomic function, or any combination of these. When a seizure occurs in the neonatal period, several special considerations arise (Table 1). A seizure in a newborn almost always reflects significant nervous system pathology, and recognizing and treating seizures properly may prevent subsequent chronic neurologic impairment. It is important not to confuse seizures with epilepsy. A seizure is a single event and may be due to a transient abnormality that will not recur (eg, hypoglycemia). Epilepsy is the condition of unprovoked recurrent seizures. Many neonatal seizures are transient events that will not progress to epilepsy. Ictal refers to clinical (based on visual observation) or electrical (based on the electroencephalogram [EEG]) activity occurring during a seizure (Table 2). Seizures occur in about 0.2% to 1.4% of all newborns. However, the incidence is much higher among certain high-risk groups. About 20% of newborns whose birthweight is less than 2500 g have seizures, with a
*Associate Neurology, Hospitals Medicine, 248 Professor of Pediatrics and

New England Medical Center and Tufts University School of Boston, MA.

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NEUROLOGY Neonatal Seizures

TABLE

1. Some

Differences

Between

Seizures

in Neonates

and

Older

Children/Adults
(if at all)

#{149} Generalized tonic-clonic seizures, jacksonian march, and typical absence seizures are seen very rarely in neonates. #{149} Many neonatal seizures involve subtle motor automatisms. #{149} Electroclinical dissociation is common in neonatal seizures (see definition in Table 3). #{149} There are very few idiopathic seizures in neonates; an extensive search for an etiology is mandatory. #{149} neonates, In focal seizures may be caused by metabolic disturbances and do not necessarily imply a focal structural lesion.

Rather, subtle and tonic seizures are seizures, an interictal EEG pattern cations and usually are not accompathought by some authorities to be nied by ictal EEG changes. Therecalled burst suppression is seen, in brainstem reflexes released by forewhich generalized bursts of highfore, tonic seizures may not be brain depression. In normal infants, epileptic seizures, but rather brainamplitude activity (bursts) are interexerts inhibitory control spersed with prolonged periods (sec- stem release phenomena. One type of the forebrain over the brain stem; when the foretonic neonatal seizure, termed tonic onds to minutes) when the EEG is resembles infantile spasms of brain is depressed, as in HIE, its inalmost flat (suppression). This pattern spasms, hibitory control over brainstem recarries an ominous prognosis, espeolder infants. The combination of flexes is diminished or released, spasms and a burst suppression cially if it persists for several days or tonic and clinical signs of subtle or tonic longer. Most infants have profound EEG is termed Ohtahara syndrome seizures appear. This hypothesis cerebral dysfunction, hence, the syn- (early infantile epileptic encephalopadrome is named early myoclonic en- thy). Most cases of Ohtahara synmight explain why EEG changes are are caused by cerebral malfor- not seen in most subtle neonatal seicephalopathy (EME). Most cases of drome and carry a very poor zures-they may not be truly epilepEME are caused by inborn errors of mations prognosis. tic, in that they are not accompanied metabolism. The most common type of neonaby paroxysmal discharge of cortical Myoclonic seizures must not be neurons that can be detected by EEG. confused with benign neonatal sleep tal seizure is the subtle type. These myoclonus, in which brief myoclonic involve signs such as ocular changes This hypothesis also would explain why even high doses of anticonvul(conjugate horizontal deviation, jerks occur during drowsiness and early stages of sleep but not during blinking, eye fluttering), oral-buccalsants fail to control many subtle or wakefulness. Benign neonatal sleep lingual movements (chewing, drooltonic seizures. An alternative explanation may be that subtle and tonic myoclonus is not accompanied by ing, sucking, tongue thrusting), EEG changes, and the neurologic cyclinglswimming limb movements, seizures are caused by paroxysmal examination and outcome are normal. apnea (usually accompanied by other discharges of neurons in the brain Tonic seizures may be generalized seizure manifestations), or autonomic stem or other structures inaccessible or, rarely, focal. Generalized tonic to scalp EEG recordings. This controchanges (blood pressure fluctuation, versy is not yet resolved but is imseizures involve extension of all tachycardia, pupil dilation). Subtle limbs, resembling decerebrate or seizures usually are not accompanied portant with regard to neonatal seizure treatment. One would not wish decorticate posturing. This type of by ictal EEG changes (except episodes of tonic eye deviation, which seizure is seen most often in severe to treat these clinical phenomena agbrain injury (HIE, intracerebral hem- often have an EEG correlate). There- gressively with anticonvulsants unless orrhage) in which the forebrain func- fore, as with tonic seizures, subtle they were truly epileptic because the tion and consciousness are proseizures may not have the same very high doses of drugs required to foundly depressed. Tonic seizures pathophysiologic basis as clonic sei- eliminate all ictal behavior could be respond poorly to antiepileptic medi- zures or seizures of older children. toxic to the infants brain.

TABLE
Electroclinical multifocal seizure: Neonatal seizure clonic seizures, generalized

2. Definitions
with both myoclonic

of Neonatal
clinical seizures, features tonic

Seizures
(Table 1) and EEG eye deviation seizures). correlates (ie, focal and

Clinical seizure: Clinically autonomic function, which epileptic (EEG correlate) article.

observed seizure activity; paroxysmal change in newborn activity, behavior, or may be correlated with EEG changes. Some authors divide neonatal seizures into and nonepileptic (no EEG correlate) types. This nomenclature is not used in this

Electrographic seizure: Seizure Clinical seizure activity without to as electroclinical dissociation.

activity EEG

recorded correlate

on EEG without or EEG seizure

clinically observable activity without clinical

changes changes

in the both

infant. are referred

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NeonawSelzur.s
Pathophysiology

NEUROLOGY

The developing brain is extraordinarCLINICAL SEIZURE TYPE EEG CORRELATION ily complex. Myelination, synaptogenesis, elaboration of dendritic proClonic: Focal or Multifocal Frequent cesses, and formation of ionic Tonic channels and neurotransmitter recepFocal Frequent tors all are occurring simultaneously. Generalized Rare Each of these processes affects the occurrence and nature of ictal activity Myoclonic in a neonate, but the exact contribuFocal or Multifocal Rare tion of each is unknown. Neonatal Generalized Frequent* seizures often are fragmentary and SubtlelMotor Automatisms Raret focal, probably because immature myelination prevents their generaliza*Especially when these resemble infantile spasms. tion and rapid spread. Several obsertExcept for tonic eye deviation, which frequently hasEEG correlate. an vations could explain the increased susceptibility of the immature brain to seizures. In general, hyperexcitability leading to seizures could occur when either the level of brain excitation increases or the level of inhibition decreases. Excitatory neurotransmitters and receptors appear to mature slightly earlier than inhibitory ones, which may account partially for the enhanced seizure susceptibility of s-.the neonatal brain. Additionally, the #{241}ghtamjrki developing brain is unique in having many more electrical synapses (gap junctions) than the mature brain. These electrical synapses allow rapid AJVA direct current flow from one neuron to another and could enhance the synchrony of neuronal firing. Finally, the immaturity of supporting glial cells could contribute to heightened epileptogenicity by incompletely buffering the excess extracellular potassium ions that accumulate during rapid neuronal discharge, which could lead to further neuronal excitation. Seizures, especially prolonged ones, may diminish the energy supply of the brain and may lead to local ischemia and cell death. Prolonged seizures also affect oxygenation, acidbase status, and cardiovascular function adversely, and these systemic factors can lead to additional hypoxic-ischemic damage. Seizures also can cause neuronal death by an excitotoxic mechanismexcessive release of endogenous neurotoxic compounds during a seizure act at certain subtypes of glutamate recepFIGURE 1. EEG recordings from a 19-day-old female who has neonatal seizures tors and can cause overexcitation, secondary to severe H1E. Figure JA shows the build-up of high-voltage rhythmic excessive influx of calcium ions, and spikes in the left hemisphere (arrow), accompanied by repetitive jerking of the right consequent cell death. The susceptiarm and hand (electroclinical seizure). Figure lB shows an electrical seizure arising to excitotoxicity, however, may from the opposite hemisphere 8 minutes later, this time without any clinical changesbility be age-dependent, with the immature (electrographic seizure).
250 Pediatrics in Review Vol. /6 No. 7 July /995

TABLE

3. Types

of Neonatal Seizures

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r
I
NeonMS&zwes
than more the resistant mature to brain. brain somewhat neurotoxicity

TABLE
#{149} Hypoxic-ischemic

4. Etiologies
encephalopathy

of Neonatal

Seizures

Etiologies infection #{149} Central nervous system -Meningitis Almost any pathologic insult can pro-Encephalitis duce neuronal hyperexcitability and -Brain abscess cause a neonatal seizure (Table 4). The spectrum of neonatal seizure eli#{149} Intracranial hemorrhage or hrombosis t (arterial or venous) ologies has shifted over time. Several -Intraventricular hemorrhage (mainly in preterm infants) decades ago, late hypocalcemia (oc-Intracranial, subdural, or subarachnoid hemorrhage (often related to curling at 4 to5 days of age) due to trauma) a low calcium/phosphate ratio in infant formula (from improper mixing) #{149} Central nervous system malformations was a frequent cause of neonatal sei#{149} Acute metabolic disorders zures; late hypocalcemic seizures -Hypocalcemia now are rare. On the other hand, the -Hypoglycemia survival of early preterm infants has -Hypomagnesemia opened new categories of etiology for -Hypoor hypernatremia neonatal seizure. The occurrence of a neonatal seizure mandates an exten#{149} Inborn errors of metabolism sive search for an etiology because -Aminoacidopathies (phenylketonuria, maple syrup urine disease, very few neonatal seizures are idioketotic or nonketotic hyperglycinemia) pathic or benign. Furthermore, many -Organic acidopathies (proprionic acidemia, methylmalonic acidemia) neonatal seizures have treatable etiol-Urea cycle disorders ogies. The most common cause of -Biotinidase deficiency neonatal seizures is asphyxia, with -Molybdenum cofactorlsulfite oxidase deficiency HIE accounting for approximately -Glucose-transporter protein deficiency 50% of neonatal seizures. Another #{149} Peroxisomal disorders 15% are due to intracranial hemor-Neonatal adrenoleukodystrophy rhage. Infections, cerebral malforma-Cerebrohepatorenal (Zellweger) syndrome tions, acute and inborn metabolic disturbances, toxins, and other causes #{149} Neurocutaneous disorders each account for about 5% to 10% -Tuberous sclerosis each. The timing of the seizure with -Incontinentia pigmenti respect to postnatal age can give -Sturge-Weber syndrome clues to the etiology (Table 5). Nota-Neurofibromatosis (seizures rare in newborn period) bly, seizures due to HIE characteristically occur within the first 24 hours. #{149} Mitochondrial disorders Occasionally, no seizure etiology is #{149} Toxins apparent after extensive evaluation, -Maternal (cocaine, heroin, methadone, barbiturates) and the neonate looks well and is -Local anesthetic injection during delivery neurologically normal between sei-Kernicterus (bilirubin encephalopathy) zures. Such an infant may have a -Propylene glycol benign neonatal seizure (either familial or idiopathic). The familial variety #{149} Hypertensive encephalopathy usually begins in the first 3 days of #{149} Pyridoxine (vitamin B6) dependency life, and a family history of seizures in the neonatal period always is ob#{149} Benign neonatal seizures tamed. The idiopathic type also is -Benign familial neonatal convulsions (BFNC) called fifth day fits because the -Benign idiopathic neonatal convulsions (BINC or fifth day fits) majority first occur on the fifth day of life (80% between days 4 and 6). Most infants who have benign neonaand physical abnormalities (Table 6). tal seizures have a favorable neuroderecommended. It must be emphasized velopmental outcome, although up to that these to determine whether syndromes are diagnoses ofIt is important 14% who have the familial type later exclusion. any prenatal compromise has ocdevelop epilepsy. Because most incurred (congenital infection, intrafants outgrow benign seizures, it is uterine asphyxia), whether perinatal Diagnosis not clear that long-term anticonvulrisk factors were present (hypoxia, sant treatment is necessary; treatment The history and physical examination trauma), and whether a genetic prein the neonatal period, however, is should identify possible risk factors disposition exists (family history of
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I$I4.y

TABLE FIRST 24 HOURS


Hypoxic-ischemic Meningitis Direct drug effects injection) dependency infections virus) (except

5. Etiologies

of Neonatal 24-72
Meningitis Drug

Seizures HOURS

at Various

Postnatal

Ages >72 HOURS

encephalopathy

Meningitis Herpes Hemorrhage simplex virus

withdrawal

(inadvertant

Hemorrhage

anesthetic Pyridoxine TORCH simplex

Inborn herpes Cerebral

metabolic malformations

errors

Inborn

metabolic

errors

Late hypocalcemia (high phosphate load of improperly prepared formula) Cerebral BFNC, malformations BINC

Hemorrhage/thrombosis Acute metabolic causes

BFNC

neonatal seizures). The physical ex- Treatment quired to eliminate all electrographic amination should focus on obvious seizure activity likely would be toxic. A newborn seizure is frightening to The primary reasons to treat neocongenital anomalies and abnormal witness, and the tendency of some neurologic signs. Seizure activity can natal seizures are to prevent further pediatricians is to treat the infant imseizures and brain damage and to be differentiated at the bedside from mediately with anticonvulsant medireduce seizure-induced physiologic a nonseizure phenomenon such as cation. However, this urge must be jitteriness (Table 7). abnormalities. Some animal models resisted and a logical approach folThe initial clinical and laboratory show that the neonatal brain may be The first step is to ensure sta- relatively resistant to the adverse efevaluation should seek to clarify the lowed. of vital functions, such as air- fects of seizures. All anticonvulsants etiology and classify the seizure type. bility way, breathing, and circulation. Then potentially It is essential to rule out treatable have undesirable side efappropriate medical management metabolic causes (via blood chemisfects. On the other hand, prolonged should be initiated, such as correction tries), infections (via cerebrospinal seizure activity can produce neuronal of metabolic abnormalities (Table 8) death fluid analysis, blood cell count, and independent of metabolic facand institution of antibiotics. The cultures), and intracranial hemortors. Therefore, the decision to treat a rhages and cerebral malformations next step is to determine whether neonate with anticonvulsants should (via a brain imaging study). Based on specific on the severity, duration, anticonvulsant therapy is in- be based findings from the history, physical and frequency of seizures. Unfortudicated. Neurologists agree uniformly examination, and initial laboratory specific guidelines for deterthat electroclinical seizures should be nately, examinations, other laboratory studies treated. what is severe, prolonged, However, consensus is lack- mining might be indicated, such as those that ing about or frequent are not available. The treatment of clinical seiscreen for inborn errors in amino or zures pediatrician must weigh the relative without an electrographic correorganic acid pathways, urea cycle risks and benefits before embarking late and pure electrographic seizures. on pharmacologic treatment. defects, or biotinidase activity. A rare As discussed previously, some types though treatable cause of neonatal Figure 2 outlines the treatment of of neonatal seizures may not be neonatal seizures. The usual first seizures is pyridoxine (vitamin B6) caused by excessive discharge of corchoice of anticonvulsant is phenobardependency. Pyridoxine is a cofactor tical neurons, but rather by release of in the synthesis of the inhibitory bital, although some physicians favor brainstem reflexes. Among such ina benzodiazepine such as lorazepam neurotransmitter gamma-aminobutyric fants, very high doses (toxic range) or diazepam. Lorazepam often is preacid; its absence can cause seizures of anticonvulsants likely will be rebecause of a lack of inhibition in the ferred over diazepam because of its quired to suppress the clinical ictal much longer half-life. For adequate CNS. Every infant who has refractory activity, and the medication actually neonatal seizures should receive a blood levels (20 to 40 tg/mL), a full harm than the seizures. trial of pyridoxine during EEG moni- may do more 18- to 20-mg/kg phenobarbital load Thus, it might not be beneficial to toring. In infants who have pyridoxmust be given. Thereafter, additional treat tonic posturing or subtle autome-dependent seizures, the seizures 5- to 10-mg/kg boluses may be given matisms. Similarly, it is unclear how until a serum often stop and the EEG normalizes level of 40 to 50 tg/mL electrographic seizures within minutes of administration of aggressive is reached. Additional phenobarbital that have no clinical correlate should the vitamin. Oral vitamin B6 supplerarely will achieve seizure control be treated; many infants experiencing without affecting the infants mental mentation then can be implemented to prevent further seizures and perthese seizures are very ill, and the status and neurologic examination manent neurologic dysfunction. high levels of anticonvulsants readversely; therefore, if seizures con

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NEUROLOGY Neonatal Seizures

TABLE

6. Evaluation

of a Neonate

Who Has

Seizures

History Pregnancy #{149} Maternal drug use (hypnotics, narcotics, analgesics) #{149} Maternal infection, bleeding, or trauma #{149} Maternal blood pressure, toxemia, preeclampsia, #{149} Fetal movement-decreases or paroxysmal increases #{149} Polyhydramnios/oligohydramnios Labor #{149} Duration, complications #{149} Fetal monitoring #{149} Fetal heart rate and reactivity

Delivery #{149} Meconium #{149} Need for oxygen or resuscitation eclampsia #{149} Nuchal cord #{149} Prolonged or precipitous #{149} Forceps or trauma #{149} Apgar scores Family history of seizures, especially period

in

newborn

Physical Examination Vital signs #{149} Temperature control #{149} Breathing pattern #{149} Blood pressure Weight, length-appropriateness for gestational age Head circumference (microcephaly may imply cortical dysgenesis or intrauterine infection) Unusual odor of sweat or urine #{149} Musty (phenylketonuria) #{149} Maple syrup (branched-chain ketonuria) #{149} Sweaty feet (isovaleric acidemia) Dysmorphisms (might suggest brain malformation) Scalp: hematomas, needle marks (suggesting local anesthetic infiltration during labor) Fontanelle: size, bulging Cranial bruits: arteriovenous malformation Eyes #{149} Chonoretimtis-toxoplasmosis, cytomegalovirus, rubella #{149} Retinal lacunae, microphthalmia-Aicardi syndrome #{149} Cataracts-rubella, galactosemia, chromosome anomalies Skin #{149} Facial angioma (trigeminal distribution)-Sturge-Weber syndrome #{149} Caf#{233}-au-lait spots-neurofibromatosis #{149} Erythematous bulla-incontinentia pigmenti #{149} Vesicles-herpes simplex virus #{149} Jaundice Neurological examination #{149} Mental status-alertness, sleep/wake cycling, visual fixation #{149} Cranial nerves-eye movements/deviation #{149} Motor-tone abnormalities, focal or generalized -hemiparesis -twitching or jerking movements -jitteriness/tremor #{149} Tendon reflexes #{149} Infantile reflexes-Moro, root, suck, palmar and plantar grasps, asymmetric tonic neck #{149} Sensory-focal deficits

reflex

Laboratory

Studies*

#{149} Serum electrolytes, glucose, BUN, calcium, magnesium, phosphate, bilirubin, ammonia #{149} Complete blood count with differential and platelet count #{149} Urinalysis and urine toxicology screen #{149} Urine for 2,4-dinitrophenilhydrazine, reducing substances #{149} Arterial blood gas #{149} Blood culture (bacterial, viral), TORCH titers #{149} Blood and urine for amino and organic acids, lactate/pyruvate #{149} Cerebrospinal fluid-glucose, protein, cell count, Gram stain, bacterial and viral cultures, for viral antigens, lactate/pyruvate, glycine #{149} EEG #{149} Imaging study of brain: ultrasonography plus computed tomography or magnetic resonance
*W,, clinically indicateS Additional testing will be guided by initial evaluation.

latex

agglutination

imaging

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NEUROLOGY

...

Neonatal TABLE

Seizures 7. Bedside Neonatal Determination Seizures and of Differences Jitteriness Between

tinue, another medication should be added. Phenytoin ordinarily is added if phenobarbital fails to stop seizures; these two drugs in combination will NEONATAL stop up to 80% of neonatal seizures. SEIZURE JITTERINESS Because both phenobarbital and pheAll extremities involved Rare Common nytoin compete for hepatic enzymes, the addition of phenytoin may inSpeed of movements Slow Fast crease the level of phenobarbital. Phenytoin can depress myocardial Stimulation induces movements Rare Common function, so it always must be adminMovements stop with restraint or Rare Common istered slowly, with concurrent elecpassive flexion trocardiographic monitoring. If seizures stop with the administration of Eye movement or gaze abnormality Common Rare phenobarbital or phenytoin, mainteAutonomic signs or symptoms Common Rare nance doses should be started and the infant weaned as soon as possible. If seizures do not stop after administration of phenobarbital and phenyNeonatal Seizure tom, the infant is likely to be in staSz continue tus epilepticus, defined as continuous ictal activity for at least 30 minutes Correct Metabolic Parameters (Table8) or very frequent shorter seizures over 30 or more minutes. Because such Sz continue prolonged seizures are associated with deleterious neurologic consePhenobarbital 18-20 mg/kg IV or quences, aggressive pharmacologic Lorazepam 0.05-0.1 mg/kg IV therapy is indicated. A trial of pyridoxine (50 to 100 mg IV) should be Sz stop Szcontinue given with concurrent EEG monitorMaintenance PHB Additional PHB up to 60 mg/kg total, ing, as described previously. Several in 5-10 mg/kg boluses every 5-10 mm. 3-5 mg/kg/d IV or options for treating status in new(have ventilation equipment available) p0t divided bid borns are listed in Figure 2. In addition, I have found that oral acetazolSzstop Sz continue amide often is a useful adjunctive Attempt to wean before PHT 15-20 mg/kg drug in refractory newborn status discharge from nursery IV at <50 mg/mm; epilepticus. Further information about or by age 3 mo. monitor EKG, bp the pharmacologic treatment of neonatal seizures can be found in the Suggested Readings. Anticonvulsants should be disconSz stop Sz continue tinued at the earliest appropriate time, preferably prior to discharge from the Maintenance PHT** Pyridoxinettt nursery. Discontinuation while still in 5 mg/kg/d IV 50-100mg IV the nursery allows observation for divided bid during EEG recurrent seizures. Infants who have persistent seizures obviously need long-term treatment. Infants who Sz stop Sz continue have been seizure-free following transient seizures likely will be weaned successfully from anticonvulPyridoxine Consider DZP 10 mg/d 0 MDZ sants, especially if the neurologic PAL status, interictal EEG, and brain imLIDO Crushed tablets are often tolerated better than elixir. aging study are normal. However, ACZ Due to poor absorption, oral PHT is not routinely recommended. most infants fall between these two Pyridoxine may be given at this point or earlier. extremes, and the guidelines for discontinuation of medication in this FiGURE 2. Treatment algorithm for neonatal seizures. Sz: seizure; PHB: phenobarbital; group are less clear. In general, unPHT: phenytoin; MDZ midazolam; DZP: diazepam; PRL paraldehyde; UDO: lidocaine; less the child has ongoing seizures or ACZ acetazolamide. Dosages-DZP: 0.1-0.2 mg/kg bolus, may repeat 1-3 times or begin an EEG showing frequent paroxys0.2-0.8 mg/kg/h IV drip; MDZ: 0.2-0.4 mg/kg load and 0.1-0.3 IV mg/kg/h IV drip; PRL: mal discharges, a trial weaning at 0.3 mUkg diluted 1:2 in mineral oil PR; LIDO: 2 mg/kg IV load and 4-6 mg/kg/h IV 3 months is reasonable. Phenobarbital drip; ACZ: 10-30 mg/kg/d divided hid-tid, P0.
* **

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NEUROLOGY

Neonatal

Seizures

TABLES.
ABNORMALITY
Hypoglycemia Serum <20 <30 <40 age Serum <7.5 <8.0

Correction
DEFINITION

of Acute

Metabolic

Abnormalities
CORRECTION

glucose: mg/dL (preterm) mg/dL (term) mg/dL (after 3 days of at any gestational age) calcium: mg/dL mg/dL

0.25-0.5 g/kg 10% dextrose kg/mm (approximately mm; repeat as necessary)

in 1-2

water mL/kg

at 8 mg/ over 20

Hypocalcemia*

(preterm) (term)

10 mg/kg elemental calcium as a 10% calcium gluconate solution by slow IV dript (1-2 mLikg at 1 mL/min; may repeat at approximately 10-mm intervals as needed) 0.1-0.2 mL/kg intravenously of50% magnesium or intramuscularlyt sulfate

Hypomagnesemia

Serum <1.5
not respond to monitoring.

magnesium: mg/dL
unless concurrent hypomagnesemia

*Hypocalcemia will tWjgh electrocardiographic

therapy

also

is correcteS

dation as well. Most infants who have subarachnoid hemorrhage, late-onset hypoglycemia, or benign neonatal seizures have a normal outcome. Prognosis The risk of future epilepsy in It is difficult to define the prognosis infants who have neonatal seizures varies according to etiology, the for neonatal seizures precisely because reported studies vary widely in number of days on which seizures patient population, seizure etiologies, are observed, and the EEG pattern. gestational ages, and seizure type and The risk is as high as 40% if seizures classification. Overall, the mortality are seen on 3 or more days,50% if in infants who have neonatal seizures electrographic seizures are recorded, has decreased, although it remains and more than 80% in cases of quite high for certain etiologies cerebral dysgenesis. (severe HIE, cerebral dysgenesis, inSome EEG patterns also are progtracranial hemorrhage). Mortality nostic. In general, the EEG backprimarily is due to the underlying ground is more important than the disorder. presence of spikes in determining Among survivors, the outcome of prognosis. Electrocerebral silence neonatal seizures primarily depends (flat-line), burst suppression, or abon the etiology, suggesting that it is normally low background voltages the underlying brain insult rather than portend abnormal neurologic outcome seizure activity per se that determines in nearly all cases. Mild or focal prognosis. Many neonatal seizures background abnormalities have an stop once the acute encephalopathy intermediate prognostic value. Spike resolves. The worst outcome (in discharges appearing on an otherwise terms of subsequent epilepsy, static normal background usually predict a encephalopathy, and mental retardafavorable outcome. Infants who have tion) is seen in major cerebral malelectrographic seizures but no clinical formations and severe intraventricular manifestations may have a slightly hemorrhage (0% and 10% normal worse prognosis than those who have outcomes, respectively). HIE (mildelectroclinical seizures. Among seimoderate), infections, and early hyzure types, generalized myoclonic poglycemia have an intermediate and tonic seizures are associated with prognosis (about 50% normal outthe worst prognosis. Seizures that are come). Infants who have perinatal refractory to multiple anticonvulsants asphyxia and develop epilepsy later and that persist for several days are are likely to exhibit motor abnormaliassociated with a poor prognosis, but ties (cerebral palsy) and mental retar- again, the underlying brain insult is

should be I month.

weaned

slowly

over

about

the primary determinant of seizures and neurodevelopmental outcome.

both

SUGGESTED

READING

Camfield PR, Camfield CS. Neonatal seizures: a commentary on selected aspects. J Child Neural. 1987;2:244-25 I Hahn iS. Controversies in treatment of neonatal seizures. Pediatr Neurol. 1993;9: 330-331 Horton EJ, Snead OC HI. Diagnosis of neonatal seizures. Semin Neurol. I 993; 13: 48-52 Miles DK, Holmes GL. Benign neonatal seizures. J Clin Neurophysiol. 1990;7:369379 Mizrahi EM, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 1987;37: 1837-1844 Moshe 5L. Epileptogenesis and the immature brain. Epilepsia. 1987;28(suppl l):53-515 Rust R5, Volpe ii. Neonatal seizures. In: Dodson WE, Pellock JM, eds. Pediatric Epilep.cy: Diagnosis and Therapy. New York, NY: Demos Publications; 1993 Scher MS. Painter MJ, Bergman I, et at. EEG diagnosis of neonatal seizures: clinical correlations and outcome. Pediatr Neurol. 1989;5: 17-24 Shewmon DA. What is a neonatal seizure? Problems in definition and quantification for investigative and clinical purposes. J Clin Neurophysiol. 1990;7:315-368 Volpe ii. Neonatal seizures: current concepts and revised classification. Pediatrics. I 989; 84:422-428 Volpe JJ. Neurology of the Newborn. 3rd ed. Philadelphia, Penn: WB Saunders Co; 1995 Wasterlain CG, Vert P. Neonatal Seizures. New York, NY: Raven Press; 1990 Yager JY, Vanucci RC. Seizures in the first week of life. In: Murphy JV, Dehkarghani F, eds. Handbook of Pediatric Epilepsy. New York, NY: Marcel Dekker, mc; 1993

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Neonatal Seizures Carl E. Stafstrom Pediatrics in Review 1995;16;248 DOI: 10.1542/pir.16-7-248

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