CHAPTER 611.

Neonatal
Seizures
 TABLE OF CONTENTS

DEFINITION AND
01. TYPES 04. DIAGNOSIS

02. PATHOPHYSIOLOGY 05. PROGNOSIS

03. ETIOLOGY 06. TREATMENT

 01.
DEFINITION AND TYPES
 INTRODUCTION
● Incidence: 5.75% for infants BW <1500g and 0.28% in
infants BW 2500-3999 g.
● Most distinctive indicator of neurological problem
● There it is important to:
○ RECOGNIZE
○ DETERMINE THE CAUSE
○ TREAT APPROPRIATELY
Definition

A seizure is a transient occurrence of signs

and/or symptoms resulting from abnormal
excessive or synchronous neuronal activity
in the brain.
 Types of Neonatal Seizures

SUBTLE CLONIC TONIC

SPASMS MYOCLONIC
 Types of Neonatal Seizures
Spasms, Focal Tonic, Motor automatisms and Subtle,
Focal Clonic, Generalized Tonic,
Generalized Myoclonic Multifocal Myoclonic

-with electrographic discharges -frequently not associated with

(epileptic seizures) discharges

- secondary to brain injury

 Subtle Seizures
● Premature > full term infants

● May present as:

○ Transient eye deviations, nystagmus or blinking
○ Mouthing
○ Abnormal extremity movements (rowing, swimming,
bicycling, pedaling, and stepping)
○ Fluctuations in heart rate
○ Hypertensive episodes
○ Apnea
 Clonic Seizures

Multifocal clonic seizures

● Incorporate several body parts
● Migratory in nature (migration follows a non-Jacksonian trend)

Generalized clonic seizures

● Bilateral, symmetric, and synchronous movements
● Uncommon in the neonatal period (due to decreased connectivity
associated with incomplete myelination at this age)
 Clonic Seizures
Focal clonic seizures

● Repetitive, rhythmic contractions of the muscle group of the limbs,

face or trunk
● Unifocal or multifocal
● May occur synchronously or asynchronously in muscle groups on
one side of the body
● May occur simultaneously but asynchronously on both sides
● Cannot be suppressed by restraint
● Pathophysiology: epileptic
 Tonic Seizures
Focal tonic seizures
● Sustained posturing of single limbs
● Sustained asymmetric posturing of
the trunk
● Sustained eye deviation
● Cannot be provoked by stimulation
or suppressed by restraint
● Pathophysiology: epileptic
Generalized tonic seizures
● More common
● Sustained symmetric posturing of
limbs, trunk, and neck
● May be flexor, extensor, or mixed
extensor/flexor
● May be provoked or intensified by
stimulation
● May be suppressed by restraint or
repositioning
● Presumed pathophysiology:
nonepileptic
 Spasms
● Sudden generalized jerks (1-2 sec), shorter in duration,
usually associated with a single, very brief,
generalized discharge
● May be flexor, extensor, or mixed extensor/flexor
● May occur in clusters
● Cannot be provoked by stimulation or suppressed by
restraint
● Pathophysiology: epileptic
 Myoclonic Seizures
● Myoclonic seizures can be distinguished from clonic seizures by the rapidity of the
jerks (<50 msec) and by their lack of rhythmicity.

● 3 Types:
○ Focal - affect the flexor muscles of the upper extremities and are sometimes
associated with seizure activity on EEG

○ Multifocal - involve asynchronous twitching of several parts of the body and are
not commonly associated with seizure discharges on EEG.

○ Generalized - involve bilateral jerking associated with flexion of upper and

occasionally lower extremities
 Myoclonic Seizures

● 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
 Seizures vs. Jitterness

Seizures Jitterness
● Generally do not end ● Rapid motor activities,
with tactile or motor such as a tremor or
suppression. shake, that can be
● Often involve eye ended by flexion or
deviation and holding the limb.
autonomic changes. ● Usually induced by a
stimulus.
02.
Pathophysiology
I. Immature Brain

● Delay in Na+ , K+ -adenosine triphosphatase maturation

● Increased NMDA and

α-amino-3-hydroxy-5-methylisoxazole-4-propionate
(AMPA) receptor density
➔ This in turn leads to an increase permeability of
Calcium
Increased Calcium permeability

Increased excitability and

development of seizure

Long term consequence due to

perinatal hypoxia
 II. Delay in the development of inhibitory GABAergic
transmission

● GABA in the immature brain has an excitatory function because the

chloride gradient is reversed relative to the mature brain
○ Resulting to higher chloride concentration intracellularly than
extracellularly

● Thus, opening of the chloride channels in the immature brain results in

depolarizing the cell and not in hyperpolarizing it
 03.
Etiology
 Etiology
Brain Malformations

Intracranial Infections 10%

10%

50-60%
Vascular Events 10-20% Hypoxic- Ischemic
Encephalopathy
 Hypoxic- Ischemic Encephalopathy

● Most common cause of neonatal seizures (50–60%)

● Seizures secondary to this encephalopathy occur within 12 hours of birth

● Neonates lack the extensive autoregulatory mechanisms of cerebral blood

flow regulation.
 Vascular Events
● Include intracranial bleeds and ischemic strokes (10–20%)
○ 3 types of hemorrhage can be distinguished:
■ Primary subarachnoid hemorrhage
■ Germinal matrix–intraventricular hemorrhage
■ Subdural hemorrhage
● Arterial strokes or venous sinus thrombosis
○ present with seizure
○ Diagnosed with neuroimaging
 Intracranial Infections

● Bacterial and nonbacterial infections (5–10%)

● May include:
○ Bacterial meningitis
○ TORCH (toxoplasmosis, other infections, rubella,
cytomegalovirus, herpes simplex virus) infections
○ Herpes simplex encephalitis
 Brain Malformations
● Brain malformations (5-10%)
● Aicardi syndrome
○ Triad:
1. Neurologic clinical abnormalities (spasms)
2. Agenesis of the corpus callosum
3. Ophthalmological abnormalities (chorioretinal lacunae)
○ Tonic convulsive or limited clonic spasms - most frequent
manifestations;start in the first year of life
○ Spasms are predominantly asymmetrical, with hemiparesis or
hemiplegia on the side that is more affected
 Metabolic Disturbances
● Metabolic disturbances include disturbances in:
○ Glucose
○ Calcium
○ Magnesium
○ Other electrolytes, amino acids, or organic acids
○ Pyridoxine dependency
 Metabolic Disturbances

● Hypoglycemia
○ Common in small neonates and neonates whose mothers are
diabetic or prediabetic
○ Neurologic symptoms correlates with duration of hypoglycemia
 Metabolic Disturbances

● Hypocalcemia
○ Occurs in two peaks:
● First: Corresponds to low birth-weight infants; apparent
on 2-3 days of life
● Second: Term infants who consume milk that has an
unfavorable ratio of phosphorus to calcium and
phosphorus to magnesium
 Metabolic Disturbances

● Other electrolyte Imbalances such as hypomagnesemia assoc.

to hypocalcemia and hyponatremia secondary to inappropriate
antidiuretic hormone secretion or water intoxication

● Local anesthetic intoxication seizures

○ From local anesthetics that are inadvertently administered
into the infant's scalp
 Metabolic Disturbances
● Disturbances in amino acid or organic acid metabolism
○ usually associated with acidosis and/or hyperammonemia

● Pyridoxine and pyridoxal dependency disorders

○ can cause severe seizures which are often multifocal clonic,
usually start during the 1st few hr of life
 Drug Withdrawal
● Incriminated drugs include barbiturates, benzodiazepines,
heroin, and methadone.
● Caused by the neonate's passive addiction and drug
withdrawal after birth
● Seizures appear during the first 3 days of life
● Infant may be jittery, irritable, and lethargic and can have
myoclonus or frank clonic seizures
 Neonatal Seizure Syndromes

1. Benign neonatal convulsions (5th-day fits)

● Usually apneic, and focal motor seizures that start around the 5th day
of life
● Interictal EEG shows a distinctive pattern called theta pointu alternant
(runs of sharp 4- to 7-Hz activity) and ictal EEG shows multifocal
electrographic seizures
 Neonatal Seizure Syndromes

2. Benign familial neonatal seizures

● Onset at 2-4 days of age and usually remit at 2-15 weeks of age
● Consist of ocular deviation, tonic posturing, clonic jerks, and, at times,
motor automatisms
● Begins on the 2nd to 3rd day of life, with a seizure frequency of
10-20/day.
 Neonatal Seizure Syndromes
Early myoclonic encephalopathy and early infantile epileptic
encephalopathy (Ohtahara syndrome)

○ Uncommon type of epilepsy

○ Characterized by intractable seizures and developmental delays
○ Onset - first 3 months of life (most often within the first 10 days of life)
○ Tonic seizures predominate, myoclonic seizures are uncommon,
distinguishing this syndrome from early myoclonic encephalopathy
 According to Common Age of Presentation

AGES 1-4 DAYS

● Hypoxic-ischemic encephalopathy
● Drug withdrawal, maternal drug use of narcotic or barbiturates
● Drug toxicity: lidocaine, penicillin
● Intraventricular hemorrhage
● Acute metabolic disorders
● Inborn errors of metabolism
● Pyridoxine dependency and pyridoxical 5 phosphate dependency
AGES 4-14 DAYS

● Infection
● Metabolic disorders
● Drug withdrawal, maternal drug use of narcotics or barbiturates
● Benign neonatal convulsions, familial and nonfamilial
● Kernicterus, hyperbilirubinemia
● Developmental delay, epilepsy, neonatal diabetes syndrome
AGES 2-8 WEEKS
● Infection
● Head injury
● Inherited disorders of metabolism
● Malformations of cortical development
● Tuberous sclerosis
● Sturge-Weber syndrome
 04.
Diagnosis
● Prenatal and postnatal history Could correctly diagnose seizure
● Physical Examination disorders in some cases

● EEG (main tool for diagnosis)

○ Can show epileptiform activity (e.g., sharp waves) between the
seizures (suggesting an increased risk for seizures)
○ Confirm electrographic seizure activity if a clinical seizure is
recorded
○ Electroclinical dissociation - electrographic seizures
that occur without observed clinical signs
● Amplitude-integrated EEG (aEEG) monitoring

○ Used as an adjunct to conventional EEG monitoring and provides a

bedside graphic representation of a neonate's electrocerebral activity
○ Aid in earlier seizure identification
○ Examples of situations:
■ Hypoxic-ischemic injury
■ Intracranial infarct or hemorrhage, or CNS infection
■ Infants with congenital cerebral malformations
■ Infants in whom clinical events suspected to be seizures
● Neurologic Examination
○ TORCH infection may show chorioretinitis
○ Aicardi syndrome is associated with coloboma of the iris and retinal
lacunae

● Inspection of the skin

○ hypopigmented lesions characteristic of tuberous sclerosis (seen best
on UV light examination)
○ Associated with generalized myoclonic seizures early in life

● Blood determination
○ Glucose levels
○ Serum calcium, magnesium and other electrolytes
○ Blood urea nitrogen (BUN)
● Lumbar puncture
○ Indicated in neonates with seizures (unless the cause is obviously
related to a metabolic disorder or attributable to a structural etiology
such as hypoxic-ischemic injury or intracranial hemorrhage)
○ Findings can indicate a bacterial meningitis or aseptic encephalitis
● Inborn errors of metabolism
○ Careful family history
○ In addition to having generalized clonic seizures, these latter infants
present during the first few days of life with increasing lethargy
progressing to coma, anorexia and vomiting, and a bulging fontanel
● MRI and CT Scan
○ Infants with focal seizures, suspected stroke or
intracranial hemorrhage, and severe
cytoarchitectural abnormalities of the brain (including
lissencephaly and schizencephaly)
○ Recommended for all neonates with seizures
unexplained by serum glucose, calcium, or electrolyte
disorders.
 05.
Prognosis
● Mortality rates (from 40% to 20%) due to advancements in obstetric and
intensive neonatal care
● EEG was found to be highly associated with the outcome in premature
and full-term infants.
● Findings associated with poor outcomes:
○ Prolonged electrographic seizures (>10 min/hr)
○ Multifocal periodic electrographic discharges
○ spread of the electrographic seizures to the contralateral hemisphere
● Underlying etiology of the seizures is the main determinant
of outcome
○ Seizures secondary to hypoxic-ischemic
encephalopathy (have a 50% chance of developing
normally)
○ Seizures caused by primary subarachnoid hemorrhage
or hypocalcemia has better prognosis
 06.
Treatment
 Treatment
● Diagnosis and identification of the underlying etiology -
mainstay in the therapy of neonatal seizures

● Intravenous therapy and loading with an initial bolus or

starting with maintenance doses of a long-acting drug -
can be given taking into consideration the severity, duration
and frequency of the seizures
 Benzodiazepines

● Mechanism of Action:
○ Increase frequency of opening of Cl- channels
induced by GABA (GABA facilitatory action)
○ Increase binding of GABA to GABA-A receptor
 Benzodiazepines

● Lorazepam
○ Used in the acute treatment of neonatal seizures
○ Anticonvulsant effect occurs in less than 5 min and could last for
6-24 hours
○ Does not cause hypotension or respiratory depression
○ Dose:
■ 0.1 mg/kg for acute treatment of seizures
■ 0.05 mg/kg (range: 0.02-0.10 mg/kg) every 4-8 hr as a
scheduled medication
 Benzodiazepines

● Midazolam
○ Often started as a continuous infusion for refractory cases of neonatal
seizures
○ Dose: 0.05-0.15 mg/kg as an initial intravenous bolus, with a
continuous infusion of 0.5-1 μg/kg/min IV and can be gradually titrated
upward every 5 min or longer, to a maximum of approximately 33
μg/kg/min (2 mg/kg/hr), if tolerated
 Barbiturates
● Mechanism of action:
○ Enhancements of GABA-mediated inhibition (prolonged
opening of the Chloride channels)
○ Blockade of AMPA receptors
○ Direct opening of chloride channels (after high doses)
○ Blockade of Na+ and Ca++ channels (at high doses)

● Pharmacologic effects:
○ Suppression of excessive discharge of the seizure focus
○ Prevention of the spread of excitation from seizure focus
 Barbiturates
● Phenobarbital
○ First-choice long-acting drug in neonatal seizures
○ Loading dose is 20 mg/kg, if ineffective, additional doses of 5-10 mg/kg
can be given until a cumulative dose of 40 mg/kg
○ 24 hours after starting the loading dose, maintenance dose is started at
3-6 mg/kg/day,administered in two separate doses
○ Acidotic and Critically ill infants - free drug levels should be carefully
followed
Phenytoin and Fosphenytoin
 Phenytoin and Fosphenytoin

● Used as a first-line or second-line agent

● Loading dose: 20 mg/kg at a rate not to exceed 0.5-1.0 mg/kg/min
(prevent cardiac problems)
● Avoided in patients with significant heart disease and heart rate
should be monitored while administering the drug
 Phenytoin and Fosphenytoin

● Fosphenytoin
○ A phosphate ester prodrug and is preferable to phenytoin
○ Highly soluble in water and can be administered very safely
intravenously and intramuscularly, without causing injury to tissues
○ Loading dose of fosphenytoin is 15-20 PE/kg administered over 30
mins
○ Maintenance doses of 4-8 PE/kg/day can be given
 Other Medications

● Levetiracetam
○ Mechanism of Action:
○ Binds selectively to the synaptic vesicular protein SV2A
○ Modify the synaptic release of glutamate and GABA
○ Dose: 30-60 mg/kg/day of levetiracetam
 Other Medications
● Lidocaine
○ Showed a growing evidence as an effective second- or third-line agent
○ A bolus dose of 2 mg/kg is given, followed by an infusion at a rate of 4-6
mg/kg/hr
○ Should not be used in conjunction with phenytoin or fosphenytoin owing to
concern for cardiac side effects
● Bumetanide
○ Previously been used as an adjunct drug, particularly with phenobarbital,
because of its effect on the chloride gradient
Thank you!
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