neonatal seizure 2

DOI: 10.1542/pir.16-7-2481995;16;248Pediatrics in Review

Carl E. StafstromNeonatal Seizures

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FOCUS QUESTIONS1. What are the most common causes

of seizures in the newborn?

2. How do seizures in the newborndiffer from seizures in older chil-

dren and adults?3. What clinical features characterize

the various types of seizures in the

newborn period?

4. What correlations exist betweenclinical and electroencephalo-

graphic phenomena In newborninfants who have seizures?

5. What principles should guide the

use or choice of anticonvulsants

for neonatal seizures?

*Associate Professor of Pediatrics and

Neurology, New England Medical CenterHospitals and Tufts University School of

Medicine, Boston, MA.

248 Pediatrics in Review Vol. /6 No. 7 Jul’s 1995

ARTICLE

Neonatal SeizuresCarl E. Stafstrom, MD, PhD*

Definitions and EpidemiologyA seizure is a sudden, paroxysmal

discharge of a population of neuronsthat causes a transient alteration inneurologic function. This alterationmay involve abnormal motor activity,sensory symptoms, a change in thelevel of alertness, alteration in auto-nomic function, or any combination

of these. When a seizure occurs inthe neonatal period, several special

considerations arise (Table 1). A sei-zure in a newborn almost always re-flects significant nervous system pa-thology, and recognizing and treatingseizures properly may prevent subse-

quent chronic neurologic impairment.It is important not to confuse seizureswith epilepsy. A seizure is a single

event and may be due to a transientabnormality that will not recur (eg,hypoglycemia). Epilepsy is the condi-

tion of unprovoked recurrent seizures.Many neonatal seizures are transientevents that will not progress to epi-

lepsy. Ictal refers to clinical (basedon visual observation) or electrical(based on the electroencephalogram[EEG]) activity occurring during aseizure (Table 2).

Seizures occur in about 0.2% to

1.4% of all newborns. However, theincidence is much higher among cer-

tain high-risk groups. About 20% ofnewborns whose birthweight is lessthan 2500 g have seizures, with a

higher incidence among sicker pre-

term infants. Incidence also dependson etiology; as many as 50% of new-

borns who have severe hypoxic-isch-emic encephalopathy (HIE) developneonatal seizures. Mortality among

neonates who have seizures rangesfrom 15% to 40% and dependslargely on the underlying etiology.Despite the high incidence and sever-ity of neonatal seizures, controversy

abounds regarding nearly every as-pect of their diagnosis, pathophysiol-ogy, and management.

Types of Neonatal SeizuresBecause their brains are immature,neonates exhibit a somewhat differentrepertoire of ictal behaviors from

older children and adults. Neonatalseizure manifestations often are sub-tle and can change from moment tomoment. Neonatal seizures can beclassified into several clinical types,based on visual observation (Table3). Using the technique of simulta-neous video-EEG recording, it hasbeen possible to determine which ofthese clinical seizures are accompa-nied by electrical discharges on EEG(Table 3). Some clinical behaviors

that appear to be seizures do have an

EEG correlate, but many such clini-cal behaviors are not accompanied byabnormal electrical activity. These

observations suggest that the varioustypes of neonatal seizures may havedifferent pathophysiologic bases, and

each may require a different thera-peutic approach.

Figure 1 shows examples of EEG

recordings from a 19-day-old termfemale who suffered severe perinatalhypoxia and developed seizures onher first day of life. Figure lA showsa seizure originating from the lefthemisphere (central-parietal area),where there is a build-up of high-voltage rhythmic discharges. This

electrographic seizure was accompa-nied by rhythmic jerking of the rightarm and hand. Eight minutes later(Figure lB), another electrographicseizure arose independently from theopposite cerebral hemisphere, but itwas not accompanied by clinicallyobservable changes in the infant’s

behavior or autonomic function (an

example of electroclinical dissocia-tion). Thus, even in a single infant,

seizures can arise from more thanone focus (multifocal) at differenttimes. Many electrographic seizures

may be undetected clinically. Be-cause it is impractical to have contin-uous EEG monitoring in most neona-tal nurseries, clinical guidelines areneeded to determine when and howaggressively electrical seizures shouldbe treated.

The most easily recognized varietyof neonatal seizure is the clonic sei-zure, which involves rhythmic jerking

of one or more parts of the body.

Clonic seizures may be focal (involv-ing a single limb, both limbs on oneside of the body) or multifocal (eg,

left arm and right leg jerking togetheror, more commonly, independently intime). Unlike in seizures of olderchildren or adults, there very rarely isa jacksonian march or slow, sequen-tial spread of ictal activity in neona-

tal clonic seizures; rather, seizurestend to be migratory, first affectingone hand, then the opposite leg, etc.Furthermore, generalized tonic-clonicseizures that commonly are seen inolder individuals rarely if ever areseen in neonates because the imma-

ture nervous system is unable to pro-duce and sustain this type of seizure

activity. Consciousness often is pre-served in focal neonatal seizures. Fo-cal and multifocal clonic seizuresusually are accompanied by ictal dis-

charges (rhythmic spikes) on EEG. Incontrast to older patients, a focal sei-zure in a neonate does not necessar-ily imply focal brain pathology; a

generalized metabolic disturbancesuch as hypoglycemia may cause afocal seizure in a neonate.

Myoclonic seizures are character-ized by rapid isolated jerks of theentire body or can be fragmentaryand involve only certain body parts.Myoclonic seizures usually signifymassive central nervous system in-

jury such as HIE or major cerebralmalformation. In surviving infants,

myoclonic seizures may evolve intoinfantile spasms, and other graveneurologic sequelae may develop. Insome neonates who have myoclonic



TABLE 2. Definitions of Neonatal Seizures

Electroclinical seizure: Neonatal seizure with both clinical features (Table 1) and EEG correlates (ie, focal and

multifocal clonic seizures, generalized myoclonic seizures, tonic eye deviation seizures).

Clinical seizure: Clinically observed seizure activity; paroxysmal change in newborn activity, behavior, orautonomic function, which may be correlated with EEG changes. Some authors divide neonatal seizures into“epileptic” (EEG correlate) and “nonepileptic” (no EEG correlate) types. This nomenclature is not used in thisarticle.

Electrographic seizure: Seizure activity recorded on EEG without clinically observable changes in the infant.Clinical seizure activity without EEG correlate or EEG seizure activity without clinical changes both are referredto as electroclinical dissociation.

Pediatrics in Review Vol. /6 No. 7 Jul’s /995 249

NEUROLOGYNeonatal Seizures

TABLE 1. Some Differences Between Seizures in Neonates and Older Children/Adults

#{149}Generalized tonic-clonic seizures, jacksonian march, and typical absence seizures are seen very rarely (if at all)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}In neonates, focal seizures may be caused by metabolic disturbances and do not necessarily imply a focal

structural lesion.

seizures, an interictal EEG pattern

called burst suppression is seen, inwhich generalized bursts of high-

amplitude activity (bursts) are inter-spersed with prolonged periods (sec-

onds to minutes) when the EEG isalmost flat (suppression). This pattern

carries an ominous prognosis, espe-cially if it persists for several days orlonger. Most infants have profound

cerebral dysfunction, hence, the syn-drome is named early myoclonic en-cephalopathy (EME). Most cases ofEME are caused by inborn errors ofmetabolism.

Myoclonic seizures must not beconfused with benign neonatal sleepmyoclonus, in which brief myoclonic

jerks occur during drowsiness andearly stages of sleep but not duringwakefulness. Benign neonatal sleepmyoclonus is not accompanied byEEG changes, and the neurologicexamination and outcome are normal.

Tonic seizures may be generalizedor, rarely, focal. Generalized tonic

seizures involve extension of alllimbs, resembling decerebrate ordecorticate posturing. This type ofseizure is seen most often in severebrain injury (HIE, intracerebral hem-orrhage) in which the forebrain func-tion and consciousness are pro-foundly depressed. Tonic seizuresrespond poorly to antiepileptic medi-

cations and usually are not accompa-nied by ictal EEG changes. There-fore, tonic seizures may not beepileptic seizures, but rather brain-stem release phenomena. One type oftonic neonatal seizure, termed tonicspasms, resembles infantile spasms of

older infants. The combination oftonic spasms and a burst suppressionEEG is termed Ohtahara syndrome

(early infantile epileptic encephalopa-thy). Most cases of Ohtahara syn-drome are caused by cerebral malfor-

mations and carry a very poorprognosis.

The most common type of neona-

tal seizure is the subtle type. Theseinvolve signs such as ocular changes

(conjugate horizontal deviation,blinking, eye fluttering), oral-buccal-lingual movements (chewing, drool-ing, sucking, tongue thrusting),cyclinglswimming limb movements,apnea (usually accompanied by other

seizure manifestations), or autonomicchanges (blood pressure fluctuation,tachycardia, pupil dilation). Subtleseizures usually are not accompaniedby ictal EEG changes (except epi-sodes of tonic eye deviation, which

often have an EEG correlate). There-fore, as with tonic seizures, subtleseizures may not have the samepathophysiologic basis as clonic sei-zures or seizures of older children.

Rather, subtle and tonic seizures arethought by some authorities to be

brainstem reflexes released by fore-brain depression. In normal infants,the forebrain exerts inhibitory controlover the brain stem; when the fore-brain is depressed, as in HIE, its in-hibitory control over brainstem re-flexes is diminished or ‘ ‘released”,and clinical signs of subtle or tonicseizures appear. This hypothesis

might explain why EEG changes arenot seen in most subtle neonatal sei-

zures-they may not be truly epilep-tic, in that they are not accompaniedby paroxysmal discharge of cortical

neurons that can be detected by EEG.This hypothesis also would explainwhy even high doses of anticonvul-

sants fail to control many subtle ortonic seizures. An alternative expla-nation may be that subtle and tonic

seizures are caused by paroxysmaldischarges of neurons in the brain

stem or other structures inaccessibleto scalp EEG recordings. This contro-versy is not yet resolved but is im-

portant with regard to neonatal sei-zure treatment. One would not wish

to treat these clinical phenomena ag-gressively with anticonvulsants unlessthey were truly epileptic because thevery high doses of drugs required toeliminate all ictal behavior could betoxic to the infant’s brain.



NEUROLOGYNeonaw”Selzur.s

TABLE 3. Types of Neonatal Seizures

CLINICAL SEIZURE TYPE EEG CORRELATION

Clonic: Focal or Multifocal Frequent

TonicFocal FrequentGeneralized Rare

MyoclonicFocal or Multifocal RareGeneralized Frequent*

SubtlelMotor Automatisms Raret

*Especially when these resemble infantile spasms.

tExcept for tonic eye deviation, which frequently has an EEG correlate.

s-.-

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FIGURE 1. EEG recordings from a 19-day-old female who has neonatal seizures

secondary to severe H1E. Figure JA shows the build-up of high-voltage rhythmic

spikes in the left hemisphere (arrow), accompanied by repetitive jerking of the right

arm and hand (electroclinical seizure). Figure lB shows an electrical seizure arising

from the opposite hemisphere 8 minutes later, this time without any clinical changes

(electrographic seizure).

250 Pediatrics in Review Vol. /6 No. 7 July /995

Pathophysiology

The developing brain is extraordinar-

ily complex. Myelination, synapto-

genesis, elaboration of dendritic pro-

cesses, and formation of ionicchannels and neurotransmitter recep-

tors all are occurring simultaneously.

Each of these processes affects the

occurrence and nature of ictal activity

in a neonate, but the exact contribu-

tion of each is unknown. Neonatal

seizures often are fragmentary and

focal, probably because immature

myelination prevents their generaliza-

tion and rapid spread. Several obser-vations could explain the increasedsusceptibility of the immature brain

to seizures. In general, hyperexcit-

ability leading to seizures could oc-

cur when either the level of brain

excitation increases or the level of

inhibition decreases. Excitatory neu-rotransmitters and receptors appear to

mature slightly earlier than inhibitoryones, which may account partially forthe enhanced seizure susceptibility of

the neonatal brain. Additionally, thedeveloping brain is unique in having

many more electrical synapses (gap

junctions) than the mature brain.These electrical synapses allow rapid

direct current flow from one neuronto another and could enhance the

synchrony of neuronal firing. Finally,

the immaturity of supporting glial

cells could contribute to heightenedepileptogenicity by incompletelybuffering the excess extracellular po-

tassium ions that accumulate duringrapid 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 localischemia and cell death. Prolongedseizures also affect oxygenation, acid-base status, and cardiovascular func-

tion adversely, and these systemicfactors can lead to additional hy-

poxic-ischemic damage. Seizures also

can cause neuronal death by an “ex-

citotoxic” mechanism- excessive

release of endogenous neurotoxiccompounds during a seizure act at

certain subtypes of glutamate recep-tors and can cause overexcitation,

excessive influx of calcium ions, andconsequent cell death. The suscepti-bility to excitotoxicity, however, maybe age-dependent, with the immature



TABLE 4. Etiologies of Neonatal Seizures

#{149}Hypoxic-ischemic encephalopathy

#{149}Central nervous system infection-Meningitis-Encephalitis-Brain abscess

#{149}Intracranial hemorrhage or thrombosis (arterial or venous)-Intraventricular hemorrhage (mainly in preterm infants)-Intracranial, subdural, or subarachnoid hemorrhage (often related to

trauma)

#{149}Central nervous system malformations

#{149}Acute metabolic disorders

-Hypocalcemia-Hypoglycemia-Hypomagnesemia-Hypo- or hypernatremia

#{149}Inborn errors of metabolism-Aminoacidopathies (phenylketonuria, maple syrup urine disease,

ketotic or nonketotic hyperglycinemia)

-Organic acidopathies (proprionic acidemia, methylmalonic acidemia)-Urea cycle disorders-Biotinidase deficiency-Molybdenum cofactorlsulfite oxidase deficiency-Glucose-transporter protein deficiency

#{149}Peroxisomal disorders-Neonatal adrenoleukodystrophy-Cerebrohepatorenal (Zellweger) syndrome

. #{149}Neurocutaneous disorders-Tuberous sclerosis-Incontinentia pigmenti-Sturge-Weber syndrome-Neurofibromatosis (seizures rare in newborn period)

#{149}Mitochondrial disorders

#{149}Toxins-Maternal (cocaine, heroin, methadone, barbiturates)-Local anesthetic injection during delivery-Kernicterus (bilirubin encephalopathy)

-Propylene glycol

#{149}Hypertensive encephalopathy

#{149}Pyridoxine (vitamin B6) dependency

#{149}Benign neonatal seizures-Benign familial neonatal convulsions (BFNC)-Benign idiopathic neonatal convulsions (BINC or “fifth day fits”)

Pediatrics in Review Vol. 16 No. 7 July 1995 251

rI NeonMS&zwes

brain somewhat more resistant toneurotoxicity than the mature brain.

EtiologiesAlmost any pathologic insult can pro-

duce neuronal hyperexcitability andcause a neonatal seizure (Table 4).The spectrum of neonatal seizure eli-

ologies has shifted over time. Severaldecades ago, late hypocalcemia (oc-curling at 4 to 5 days of age) due toa low calcium/phosphate ratio in in-

fant formula (from improper mixing)was a frequent cause of neonatal sei-zures; late hypocalcemic seizuresnow are rare. On the other hand, the

survival of early preterm infants hasopened new categories of etiology forneonatal seizure. The occurrence of a

neonatal seizure mandates an exten-sive search for an etiology becausevery few neonatal seizures are idio-

pathic or benign. Furthermore, manyneonatal seizures have treatable etiol-

ogies. The most common cause ofneonatal seizures is asphyxia, withHIE accounting for approximately50% of neonatal seizures. Another15% are due to intracranial hemor-rhage. Infections, cerebral malforma-tions, acute and inborn metabolicdisturbances, toxins, and other causes

each account for about 5% to 10%each. The timing of the seizure withrespect to postnatal age can giveclues to the etiology (Table 5). Nota-bly, seizures due to HIE characteristi-cally occur within the first 24 hours.

Occasionally, no seizure etiology isapparent after extensive evaluation,and the neonate looks well and isneurologically normal between sei-

zures. Such an infant may have abenign neonatal seizure (either famil-ial or idiopathic). The familial varietyusually begins in the first 3 days of

life, and a family history of seizuresin the neonatal period always is ob-

tamed. The idiopathic type also iscalled ‘ ‘fifth day fits’ ‘ because themajority first occur on the fifth dayof life (80% between days 4 and 6).

Most infants who have benign neona-tal seizures have a favorable neurode-velopmental outcome, although up to

14% who have the familial type laterdevelop epilepsy. Because most in-fants outgrow benign seizures, it isnot clear that long-term anticonvul-sant treatment is necessary; treatmentin the neonatal period, however, is

recommended. It must be emphasizedthat these syndromes are diagnoses ofexclusion.

DiagnosisThe history and physical examinationshould identify possible risk factors

and physical abnormalities (Table 6).It is important to determine whether

any prenatal compromise has oc-curred (congenital infection, intra-uterine asphyxia), whether perinatalrisk factors were present (hypoxia,trauma), and whether a genetic pre-disposition exists (family history of



252 Pediatrics in Review Vol. 16 No. 7 July 1995

: �I�$�I4.y

�

TABLE 5. Etiologies of Neonatal Seizures at Various Postnatal Ages

FIRST 24 HOURS 24-72 HOURS >72 HOURS

Hypoxic-ischemic encephalopathy Meningitis Meningitis

Meningitis Drug withdrawal Herpes simplex virus

Direct drug effects (inadvertant Hemorrhage Hemorrhage

anesthetic injection)

Pyridoxine dependency Inborn metabolic errors Inborn metabolic errors

TORCH infections (except herpes Cerebral malformations Late hypocalcemia (highsimplex virus) phosphate load of improperly

prepared formula)

Hemorrhage/thrombosis BFNC Cerebral malformations

� Acute metabolic causes BFNC, BINC

neonatal seizures). The physical ex-amination should focus on obvious

congenital anomalies and abnormalneurologic signs. Seizure activity canbe differentiated at the bedside froma nonseizure phenomenon such asjitteriness (Table 7).

The initial clinical and laboratoryevaluation should seek to clarify theetiology and classify the seizure type.It is essential to rule out treatablemetabolic causes (via blood chemis-tries), infections (via cerebrospinalfluid analysis, blood cell count, andcultures), and intracranial hemor-rhages and cerebral malformations(via a brain imaging study). Based onfindings from the history, physical

examination, and initial laboratoryexaminations, other laboratory studiesmight be indicated, such as those that

screen for inborn errors in amino ororganic acid pathways, urea cycledefects, or biotinidase activity. A rarethough treatable cause of neonatalseizures is pyridoxine (vitamin B6)dependency. Pyridoxine is a cofactorin the synthesis of the inhibitoryneurotransmitter gamma-aminobutyricacid; its absence can cause seizures

because of a lack of inhibition in theCNS. Every infant who has refractoryneonatal seizures should receive a

trial of pyridoxine during EEG moni-toring. In infants who have pyridox-me-dependent seizures, the seizures

often stop and the EEG normalizeswithin minutes of administration ofthe vitamin. Oral vitamin B6 supple-mentation then can be implementedto prevent further seizures and per-manent neurologic dysfunction.

Treatment

A newborn seizure is frightening to

witness, and the tendency of some

pediatricians is to treat the infant im-

mediately with anticonvulsant medi-

cation. However, this urge must be

resisted and a logical approach fol-lowed. The first step is to ensure sta-

bility of vital functions, such as air-

way, breathing, and circulation. Then

appropriate medical management

should be initiated, such as correction

of metabolic abnormalities (Table 8)

and institution of antibiotics. The

next step is to determine whether

specific anticonvulsant therapy is in-

dicated. Neurologists agree uniformly

that electroclinical seizures should be

treated. However, consensus is lack-

ing about treatment of clinical sei-

zures without an electrographic corre-

late and pure electrographic seizures.

As discussed previously, some types

of neonatal seizures may not be

caused by excessive discharge of cor-

tical neurons, but rather by release of

brainstem reflexes. Among such in-fants, very high doses (toxic range)

of anticonvulsants likely will be re-

quired to suppress the clinical ictal

activity, and the medication actually

may do more harm than the seizures.

Thus, it might not be beneficial to

treat tonic posturing or subtle auto-

matisms. Similarly, it is unclear howaggressive electrographic seizures

that have no clinical correlate shouldbe treated; many infants experiencing

these seizures are very ill, and thehigh levels of anticonvulsants re-

quired to eliminate all electrographicseizure activity likely would be toxic.

The primary reasons to treat neo-natal seizures are to prevent furtherseizures and brain damage and to

reduce seizure-induced physiologic

abnormalities. Some animal modelsshow that the neonatal brain may berelatively resistant to the adverse ef-fects of seizures. All anticonvulsantspotentially have undesirable side ef-

fects. On the other hand, prolongedseizure activity can produce neuronaldeath independent of metabolic fac-tors. Therefore, the decision to treat aneonate with anticonvulsants should

be based on the severity, duration,and frequency of seizures. Unfortu-

nately, specific guidelines for deter-mining what is ‘ ‘severe, prolonged,or frequent’ ‘ are not available. The

pediatrician must weigh the relativerisks and benefits before embarkingon pharmacologic treatment.

Figure 2 outlines the treatment ofneonatal seizures. The usual firstchoice of anticonvulsant is phenobar-

bital, although some physicians favora benzodiazepine such as lorazepamor diazepam. Lorazepam often is pre-

ferred over diazepam because of itsmuch longer half-life. For adequateblood levels (20 to 40 �tg/mL), a full

18- to 20-mg/kg phenobarbital loadmust be given. Thereafter, additional5- to 10-mg/kg boluses may be given

until a serum level of 40 to 50 �tg/mLis reached. Additional phenobarbitalrarely will achieve seizure controlwithout affecting the infant’s mentalstatus and neurologic examinationadversely; therefore, if seizures con-



. NEUROLOGY� � � � � . Neonatal Seizures

TABLE 6. Evaluation of a Neonate Who Has Seizures

HistoryPregnancy Delivery

#{149}Maternal drug use (hypnotics, narcotics, analgesics) #{149}Meconium

#{149}Maternal infection, bleeding, or trauma #{149}Need for oxygen or resuscitation#{149}Maternal blood pressure, toxemia, preeclampsia, eclampsia #{149}Nuchal cord#{149}Fetal movement-decreases or paroxysmal increases #{149}Prolonged or precipitous

#{149}Polyhydramnios/oligohydramnios #{149}Forceps or trauma

Labor #{149}Apgar scores#{149}Duration, complications Family history of seizures, especially in newborn

#{149}Fetal monitoring period

#{149}Fetal heart rate and reactivity

Physical ExaminationVital signs

#{149}Temperature control #{149}Breathing pattern #{149}Blood pressure

Weight, length-appropriateness for gestational ageHead 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 malformationEyes

#{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 reflex#{149}Sensory-focal deficits

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, latex agglutination

for viral antigens, lactate/pyruvate, glycine#{149}EEG#{149}Imaging study of brain: ultrasonography plus computed tomography or magnetic resonance imaging

*W�,, clinically indicateS Additional testing will be guided by initial evaluation.

Pediatrics in Review Vol. 16 No. 7 July 1995 253



NEUROLOGY . ...� �.

Neonatal Seizures

TABLE 7. Bedside Determination of Differences BetweenNeonatal Seizures and Jitteriness

NEONATALSEIZURE JITTERINESS

All extremities involved Rare Common

Speed of movements Slow Fast

Stimulation induces movements Rare Common

Movements stop with restraint or Rare Common

passive flexion

Eye movement or gaze abnormality Common Rare

Autonomic signs or symptoms Common Rare

Neonatal Seizure

Sz continue

Correct Metabolic Parameters (Table 8)

Sz continue

Phenobarbital 18-20 mg/kg IV orLorazepam 0.05-0.1 mg/kg IV

Szcontinue

Additional PHB up to 60 mg/kg total,in 5-10 mg/kg boluses every 5-10 mm.

(have ventilation equipment available)

Sz stop

Maintenance PHB3-5 mg/kg/d IV orp0t divided bid

Szstop

Attempt to wean beforedischarge from nurseryor by age 3 mo.

Sz stop

Maintenance PHT**5 mg/kg/d IVdivided bid

Sz continue

PHT 15-20 mg/kgIV at <50 mg/mm;monitor EKG, bp

Sz continue

Pyridoxinettt50-100mg IVduring EEG

Sz continue

Consider DZPMDZPALLIDOACZ

Sz stop

Pyridoxine10 mg/d �0

* Crushed tablets are often tolerated better than elixir.** Due to poor absorption, oral PHT is not routinely recommended.

Pyridoxine may be given at this point or earlier.

FiGURE 2. Treatment algorithm for neonatal seizures. Sz: seizure; PHB: phenobarbital;

PHT: phenytoin; MDZ midazolam; DZP: diazepam; PRL paraldehyde; UDO: lidocaine;

ACZ acetazolamide. Dosages-DZP: 0.1-0.2 mg/kg bolus, may repeat 1-3 times or begin

0.2-0.8 mg/kg/h IV drip; MDZ: 0.2-0.4 mg/kg IV load and 0.1-0.3 mg/kg/h IV drip; PRL:

0.3 mUkg diluted 1:2 in mineral oil PR; LIDO: 2 mg/kg IV load and 4-6 mg/kg/h IV

drip; ACZ: 10-30 mg/kg/d divided hid-tid, P0.

254 Pediatrics in Review Vol. 16 No. 7 July 1995

tinue, another medication should be

added. Phenytoin ordinarily is addedif phenobarbital fails to stop seizures;

these two drugs in combination willstop up to 80% of neonatal seizures.Because both phenobarbital and phe-nytoin compete for hepatic enzymes,the addition of phenytoin may in-

crease the level of phenobarbital.Phenytoin can depress myocardial

function, so it always must be admin-istered slowly, with concurrent elec-trocardiographic monitoring. If sei-zures stop with the administration ofphenobarbital or phenytoin, mainte-nance doses should be started and theinfant weaned as soon as possible.

If seizures do not stop after admin-

istration of phenobarbital and pheny-tom, the infant is likely to be in sta-tus epilepticus, defined as continuous

ictal activity for at least 30 minutesor very frequent shorter seizures over30 or more minutes. Because such

prolonged seizures are associatedwith deleterious neurologic conse-quences, aggressive pharmacologictherapy is indicated. A trial of pyri-doxine (50 to 100 mg IV) should begiven with concurrent EEG monitor-ing, as described previously. Severaloptions for treating status in new-borns are listed in Figure 2. In addi-

tion, I have found that oral acetazol-amide often is a useful adjunctivedrug in refractory newborn statusepilepticus. Further information about

the pharmacologic treatment of neo-natal seizures can be found in theSuggested Readings.

Anticonvulsants should be discon-tinued at the earliest appropriate time,preferably prior to discharge from the

nursery. Discontinuation while still inthe nursery allows observation forrecurrent seizures. Infants who havepersistent seizures obviously needlong-term treatment. Infants whohave been seizure-free following

transient seizures likely will beweaned successfully from anticonvul-

sants, especially if the neurologicstatus, interictal EEG, and brain im-

aging study are normal. However,most infants fall between these two

extremes, and the guidelines for dis-continuation of medication in this

group are less clear. In general, un-less the child has ongoing seizures oran EEG showing frequent paroxys-mal discharges, a trial weaning at

3 months is reasonable. Phenobarbital



Pediatrics in Review Vol. 16 No. 7 Jul’s 1995 255

NEUROLOGYNeonatal Seizures

TABLES. Correction of Acute Metabolic Abnormalities

ABNORMALITY DEFINITION CORRECTION

Hypoglycemia Serum glucose: 0.25-0.5 g/kg 10% dextrose in water at 8 mg/

<20 mg/dL (preterm) kg/mm (approximately 1-2 mL/kg over 20<30 mg/dL (term) mm; repeat as necessary)<40 mg/dL (after 3 days of

age at any gestational age)

Hypocalcemia* Serum calcium: 10 mg/kg elemental calcium as a 10% calcium<7.5 mg/dL (preterm) gluconate solution by slow IV dript

<8.0 mg/dL (term) (1-2 mLikg at 1 mL/min; may repeat atapproximately 10-mm intervals as needed)

Hypomagnesemia Serum magnesium: 0.1-0.2 mL/kg of 50% magnesium sulfate<1.5 mg/dL intravenously or intramuscularlyt

*Hypocalcemia will not respond to therapy unless concurrent hypomagnesemia also is correcteS

tWjgh electrocardiographic monitoring.

should be weaned slowly over aboutI month.

PrognosisIt is difficult to define the prognosis

for neonatal seizures precisely be-cause reported studies vary widely in

patient population, seizure etiologies,gestational ages, and seizure type and

classification. Overall, the mortalityin infants who have neonatal seizureshas decreased, although it remainsquite high for certain etiologies(severe HIE, cerebral dysgenesis, in-tracranial hemorrhage). Mortality

primarily is due to the underlyingdisorder.

Among survivors, the outcome ofneonatal seizures primarily dependson the etiology, suggesting that it isthe underlying brain insult rather thanseizure activity per se that determinesprognosis. Many neonatal seizures

stop once the acute encephalopathyresolves. The worst outcome (interms of subsequent epilepsy, staticencephalopathy, and mental retarda-tion) is seen in major cerebral mal-formations and severe intraventricularhemorrhage (0% and 10% normal

outcomes, respectively). HIE (mild-moderate), infections, and early hy-poglycemia have an intermediateprognosis (about 50% normal out-

come). Infants who have perinatalasphyxia and develop epilepsy laterare likely to exhibit motor abnormali-ties (cerebral palsy) and mental retar-

dation as well. Most infants who havesubarachnoid hemorrhage, late-onsethypoglycemia, or benign neonatalseizures have a normal outcome.

The risk of future epilepsy ininfants who have neonatal seizuresvaries according to etiology, thenumber of days on which seizures

are observed, and the EEG pattern.The risk is as high as 40% if seizures

are seen on 3 or more days, 50% ifelectrographic seizures are recorded,and more than 80% in cases of

cerebral dysgenesis.Some EEG patterns also are prog-

nostic. In general, the EEG back-

ground is more important than thepresence of spikes in determiningprognosis. Electrocerebral silence

(flat-line), burst suppression, or ab-normally low background voltagesportend abnormal neurologic outcomein nearly all cases. Mild or focal

background abnormalities have anintermediate prognostic value. Spikedischarges appearing on an otherwisenormal background usually predict a

favorable outcome. Infants who haveelectrographic seizures but no clinicalmanifestations may have a slightlyworse prognosis than those who have

electroclinical seizures. Among sei-zure types, generalized myoclonicand tonic seizures are associated withthe worst prognosis. Seizures that arerefractory to multiple anticonvulsantsand that persist for several days areassociated with a poor prognosis, butagain, the underlying brain insult is

the primary determinant of bothseizures and neurodevelopmentaloutcome.

SUGGESTED READINGCamfield 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:

48-52Miles DK, Holmes GL. Benign neonatal

seizures. J Clin Neurophysiol. 1990;7:369-

379

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;7:315-368Volpe 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



DOI: 10.1542/pir.16-7-2481995;16;248Pediatrics in Review

Carl E. StafstromNeonatal Seizures

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