NEONATAL SEIZURES
Maria Theresa M. Villanos, MD
PL-2
Definition

A stereotypic, paroxysmal spell of
altered neurologic function
(behavior, motor,and/or autonomic
function)
Definition

Neonatal period limited to :
- first 28 days for term infants
- 44 weeks gestational age for
pre-term
Frequency



In US – incidence has not been
established clearly
Estimated frequency of 80-120 per
100,000 neonates/year
1-5:1000 live births
Frequency



0.5 % incidence -National Collaborative
Perinatal Project( population-based study on
54,000 FT and PT infants)
0.23% incidence- Scher, et al
(population of 41,00 infants)
Incidence of seizures higher in the neonatal
period than in any other age group
Why do neonatal seizures have
such unusual presentations?

Immature CNS cannot sustain a
synchronized, well orchestrated
generalized seizure
Perinatal Anatomical and Physiological
Features of Importance in Determining
Neonatal Seizure Phenomena
ANATOMICAL
Neurite outgrowth—dendritic and axonal ramifications—in
process
Synaptogenesis not complete
Deficient myelination in cortical efferent systems
Volpe JJ.Neonatal Seizures :Neurology of the Newborn.4th ed.
Perinatal Anatomical and Physiological Features
of Importance in Determining Neonatal Seizure
Phenomena
PHYSIOLOGICAL
In limbic and neocortical regions—excitatory synapses develop
before inhibitory synapses ( N-methyl-D-aspartate receptor
activity, gamma-aminobutyric acid excitatory)
Immature hippocampal and cortical neurons more susceptible to
seizure activity than mature neurons
Deficient development of substantia nigra system for inhibition of
seizures
Impaired propagation of electrical seizures, and synchronous
discharges recorded from surface electroencephalogram may
not correlate with behavioral seizure phenomena
______________________________________________________________________
Volpe JJ.Neonatal Seizures.In:Neurology of the Newborn.4th ed.
Probable Mechanisms of Some Neonatal
Seizures
PROBABLE MECHANISM
Failure of Na + -K + pump secondary to
 adenosine triphosphate
Excess of excitatory neurotransmitter
(eg.glutamic acid—excessive excitation)
DISORDER
Hypoxemia, ischemia,
and hypoglycemia
Hypoxemia, ischemia
and hypoglycemia
Pyridoxine dependency
Deficit of inhibitory neurotransmitter
(i.e., relative excess of excitatory
neurotransmitter)
Membrane alteration—  Na +
Hypocalcemia and
Permeability
hypomagnesemia
_________________________________________________________________
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
Classification of Neonatal
Seizures

Clinical

Electroencephalographic
Classification
I. Clinical Seizure
 Subtle
 Tonic
 Clonic
 Myoclonic
Classification
II. Electroencephalographic seizure

Epileptic

Non-epileptic
Clinical Classification
1. Subtle






More in preterm than in term
Eye deviation (term)
Blinking, fixed stare (preterm)
Repetitive mouth and tongue movements
Apnea
Pedaling and tonic posturing of limbs
Clinical Classification
2. Tonic





Primarily in Preterm
May be focal or generalized
Sustained extension of the upper and
lower limbs (mimics decerebrate posturing)
Sustained flexion of upper with extension of
lower limbs (mimics decorticate posturing)
Signals severe ICH in preterm infants
Clinical Classification
3. Clonic





Primarily in term
Focal or multifocal
Clonic limb movements(synchronous or
asynchronous, localized or often with no anatomic
order of progression)
Consciousness may be preserved
Signals focal cerebral injury
Clinical Classification
4. Myoclonic



Rare
Focal, multifocal or generalized
Lightning-like jerks of extremities
(upper > lower)
Electroencephalographic seizure
I. Epileptic

Consistently associated with electro-cortical
seizure activity on the EEG
 Cannot be provoked by tactile stimulation
 Cannot be suppressed by restraint of
involved limb or repositioning of the infant
 Related to hyper synchronous discharges of
a critical mass of neuron
Electroencephalographic
seizures
II. Non-epileptic
 No electro-cortical signature
 Provoked by stimulation
 Suppressed by restraint or repositioning
 Brainstem release phenomena (reflex)
Classification of Neonatal
Seizures
ELECTROENCEPHALOGRAPHIC SEIZURE
CLINICAL SEIZURE
COMMON
UNCOMMON
Subtle
+*
Clonic
Focal
+
Multifocal
+
Tonic
Focal
+
Generalized
+
Myoclonic
Focal, multifocal
+
Generalized
+
--------------------------------------------------------------------------------------------------------------*Only specific varieties of subtle seizures are commonly associate with simultaneous
Electroencephalographic seizure activity.
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
Does absence of EEG seizure
activity indicate that a clinical seizure
is non- epileptic?

Certain clinical seizures in the human
newborn originate from electrical seizures in
deep cerebral structures (limbic regions), or
in diencephalic, or brain stem structures and
thereby are either not detected by surfacerecorded EEG or inconsistently propagated to
the surface
Surface EEG-Silent Seizure
Can “ surface EEG-silent ” seizure in the
newborn result to brain injury?
 Can this be eliminated by conventional
anticonvulsant therapy?
 Further investigation needed

Jitteriness Versus Seizure
CLINICAL FEATURE
Abnormality of gaze or eye
movement
Movements exquisitely stimulus
sensitive
Predominant movement
Movements cease with passive
flexion
Autonomic changes
JITTERINESS
SEIZURE
O
+
+
O
Tremor
Clonic jerking
+
O
O
+
------------------------------------------------------------------------------------------------------------------
Normal Neonatal Motor Activity
Commonly Mistaken for Seizure
Activity
AWAKE OR DROWSY
Roving, sometimes dysconjugate eye movements, with
occasional nonsustained nystagmoid
jerks at the extremes of horizontal movement (contrast with
fixed, tonic horizontal deviation of eyes with or without jerking—
characteristic of subtle seizure
Sucking, puckering movements not accompanied by ocular fixation
or deviation
SLEEP
Fragmentary myoclonic jerks—may be multiple
Isolated, generalized myoclonic jerk as infant wakes from sleep
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
Etiology

It is critical to recognize neonatal seizures, to
determine their etiology, and to treat them for
three major reasons:
1. Seizures are usually related to significant
illness, sometimes requiring specific therapy
Etiology
2.Neonatal seizures may interfere with
important supportive measures, such as
alimentation and assisted respirations for
associated disorders.
3.Experimental data give some reason for
concern that under certain circumstances the
seizure per se may be a cause of brain injury.
Etiology

Clinical history provides important clue
 Family history may suggest genetic
syndrome
 Many of these syndromes are benign
 In the absence of other etiologies, family
history of seizures may suggest good
prognosis
Etiology

Pregnancy history is important
 Search for history that supports TORCH
infections
 History of fetal distress, preeclampsia or
maternal infections
Etiology

Delivery history
 Type of delivery and antecedent events
 Apgar scores offer some guidance
 Low Apgar score without the need for
resuscitation and subsequent neonatal
intensive care is unlikely to be associated
with neonatal seizures
Etiology

Postnatal history
 Neonatal seizures in infants without
uneventful antenatal history and delivery may
result from postnatal cause
 Tremulousness may be secondary to drug
withdrawal or hypocalcemia
 Temperature and blood pressure instability
may suggest infection
Comparison of prominent etiologic diagnoses of
seizures in the newborn period. (Data modified
from Mizrahi and Kellaway, 1987; Rose and
Lombroso, 1970)
Malformation
Hypoglycemia
Hypocalcemia
Meningitis
Stroke
1970
1987
Trauma
Hemorrhage
Hypoxia-ischemia
0
10
20
30
40
50
Incidence (%)
Fanaroff A, Martin R.Neonatal seizures. In:Neonatal and Perinatal Medicine, Diseases of the Fetus and Infant,6th ed
Major Etiologies of Neonatal Seizures in
Relation to Time of
Seizure Onset and Relative Frequency
Hypoxic-ischemic
encephalopathy
Intracranial
hemorrhage‡
Intracranial infection
Developmental
defects
Hypoglycemia
Hypocalcaemia
Other metabolic
Epileptic syndromes
TIME OF ONSET*
0-3 DAYS
>3DAYS
+
+
+
+
+
+
+
+
+
+
+
+
+
+
RELATIVE FREQUENCY†
PREMATURE FULL TERM
+++
+++
++
+
++
++
++
++
+
+
+
+
+
Inborn Errors of Metabolism Associated
With Neonatal Seizures
Conditions That Have a Specific Treatment
Pyridoxine (B6) dependency
Folinic acid-responsive seizures
Glucose transporter defect
Creatine deficiency
Other Conditions
Nonketotic hyperglycinemia
Sulfite oxidase deficiency
Molybdenum cofactor deficiency (combined deficiency)
Carbohydrate-deficient glycoprotein disorder
Lactic acid disorders
Mitochondrial disorders
Maple syrup urine disease
Isovaleric acidemia (sweaty feet, cheesy odor)
Inborn Errors of Metabolism
Associated With Neonatal Seizures
Other conditions












Isovaleric acidemia (sweaty feet, cheesy odor)
3-methylcrotonyl-CoA carbosylase deficiency
Propionic acidemia
Mevalonic aciduria
Urea cycle defects
Hyperornithemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome
Neonatal glutaric aciduria type ll
Biotin deficiencies, holocarboxylase synthetase deficiency
Fructose 1,6-diphosphatase deficiency
Hereditary Fructose intolerance
Menkes disease (trichopoliodystrophy
Peroxisomal disorders
NeoReviews vol.5 no.6 June 2004
Laboratory Studies to Evaluate
Neonatal Seizures
Indicated
Complete blood count, differential, platelet count;
urinalysis
Blood glucose (Dextrostix), BUN, Ca, P, Mg,
electrolytes
Blood oxygen and acid-base analysis
Blood, CSF and other bacterial cultures
CSF analysis
EEG
Laboratory Studies to Evaluate
Neonatal Seizures
Clinical Suspicion of Specific Disease
Serum immunoglobulins, TORCH antibody titers, and
viral cultures
Blood and urine metabolic studies (bilirubin,ammonia,
lactate, FECl³, reducing substance.)
Blood and urine toxic screen
Blood and urine amino and organic acid screen
CT or ultrasound scan
Metabolic Evaluation for Refractory
Neonatal Seizures
Consider individually by case specifics
Serum
Glucose
Electrolytes (sodium, potassium, chloride, carbon dioxide), blood urea nitrogen, chromium,
calcium, phosphorus, magnesium
Uric acid
Creative kinase
Serum ammonia
Lactic and pyruvic acids
Biotinidase
Amino acids
Serum carnitine, acylcarnitines
Serum transferrin
Copper and ceruloplasmin
Cholesterol
Fatty acids (short-chain, medium-chain, long-chain)
Pipecolic acid
NeoReviews vol.5 no.6 June 2004
Metabolic Evaluation for Refractory
Neonatal Seizures
Urine







Organic acids
Acylglycines
Uric acid
Sulfites
Xanthine, hypoxanthine
Guanidinoacetate
Pipecolic acid
Cerebrospinal Fluid





Cell count, glucose,protein
Lactic and pyruvic acids
Amino acids
Organic acids
Neurotransmitters
Other Studies



Skin biopsy
Muscle biopsy
Magnetic resonance imaging with magnetic resonance spectroscopy (especially for
creatine)
NeoReviews vol.5 no.6 June 2004
Treatment

Identify the underlying cause:
hypoglycemia - D10 solution
hypocalcemia - Calcium gluconate
hypomagnesemia- Magnesium sulfate
pyridoxine deficiency- Pyridoxine
meningitis- initiation of antibiotics
Treatment

To minimize brain damage
 Some controversy when to start
anticonvulsants
 If seizure is prolonged (longer than 3
minutes), frequent or associated
with cardiorespiratory disturbance
Drug Therapy For Neonatal Seizures
Standard Therapy
AED
Initial Dose
Maintenance Dose
Phenobarbital 20mg/kg
3 to 4 mg/kg per day
Phenytoin
20 mg/kg
3 to 4 mg/kg per day
Fosphenytoin 20 mg/kg phenytoin 3 to 4 mg/kg per day
equivalents
Lorazepam²
0.05 to 0.1 mg/kg
Every 8 to 12 hours
Diazepam²´
0.25 mg/kg
Every 6 to 8 hours
AED= andtiepileptic drug; lV= intravenous; lM= intramuscular; PO= oral
ªOral phenytoin is not well absorbed.
²Benzodiazepines typically not used for maintenance therapy.
³Lorazepam preferred over diazepam.
Route
lV, lM, PO
lV, POª
lV, lM
lV
lV
Acute therapy of neonatal seizures


If with hypoglycemia- Glucose 10%: 2ml/k IV
If no hypoglycemia- Phenobarbital:20mg/k IV
loading dose
If necessary : additional phenobarbital:
5 mg/kg IV to a max of 20 mg/kg
(consider omission of this additional
Phenobarbital
if with baby is asphyxiated)
Phenytoin: 20 mg/kg, IV (1 mg/kg/min)
Lorazepam:0.05-0.10 mg/kg, IV
Pharmacological properties of
Phenobarbital






Enters the CSF/brain rapidly with high efficiency
The blood level is largely predictable from the dose
administered
It can be given IM or IV(more preferred)
Maintenance therapy accomplished easily with oral
therapy
Protein binding lower in newborn—free levels of drug
are higher
Entrance to the brain increased by local acidosis
associated with seizures
Alternative Antiepileptic Drugs (AED)
for Neonatal Seizures
Intravenous AEDs
High-dose phenobarbital: >30 mg/kg
Pentobarbital: 10 mg/kg, then 1 mg/kg per hour
Thiopental: 10 mg/kg, then 2 to 4 mg/kg per hour
Midazolam: 0.2 mg/kg, then 0.1 to 0.4 mg/kg per hour
Clonazepam: 0.1 mg/kg
Lidocaine: 2 mg/kg, then 6 mg/kg per hour
Valproic acid: 10 to 25 mg/kg, then 20 mg/kg per day in 3 doses
Paraldehyde: 200 mg/kg, then 16 mg/kg per hour
Chlormethiazole: Initial infusion rate of 0.08 mg/kg per minute
Dexamethasone: 0.6 to 2.8 mg/kg
Pyridoxine (B6): 50 to 100 mg, then 100 mg every 10 minutes
(up to 500mg)
Alternative AEDs for Neonatal
Seizures
Oral AEDs
Primidone: 15 to 25 mg/kg per day in 3 doses
Clonazepam: 0.1 mg/kg in 2 to 3 doses
Carbamazepine: 10 mg/kg, then 15 to 20 mg/kg per day in 2 doses
Oxcarbamazepine: no data on neonates, young infants
Valproic acid: 10 to 25 mg/kg, then 20 mg/kg per day in 3 doses
Vigabatrin: 50 mg/kg per day in 2 doses, up to 200 mg/kg per day
Lamotrigine: 12.5 mg in 2 doses
Topiramate: 3 mg/kg per day
Zonisamide: 2.5 mg/kg per day
Levetiracetam: 10 mg/kg per day in 2 doses
Folinic acid: 2.5 mg BID, up to 4 mg/kg per day
NeoReviews vol.5 no.6 June 2004
Determinants of Duration of
anticonvulsant therapy for neonatal
seizures

Neonatal neurological examination

Cause of neonatal seizure

Electroencephalogram
Duration of anticonvulsant therapyGuidelines
Neonatal period
 If neonatal neurological examination
becomes normal discontinue therapy
 If neonatal neurological examination is
persistently abnormal,consider etiology and
obtain EEG
 In most such cases- Continue phenobarbital
- Discontinue phenytoin
- Reevaluate in 1 month
Duration of anticonvulsant therapyGuidelines
One month after discharge
 If neurological examination has become
normal, discontinue phenobarbital
 If neurological examination is persistently
abnormal,obtain EEG
 If no seizure activity on EEG, discontinue
phenobarbital
Prognosis
Two most useful approaches in utilizing outcome

EEG

Recognition of the underlying neurological
disease
Prognosis of Neonatal seizures in relation
to EEG
EEG BACKGROUND
Normal
Severe abnormalities†
Moderate abnormalities‡
NEUROLOGICAL SEQUELAE(%)
10
90
~50
Based primarily on data reported by Rowe JC, Holmes GL, Hafford J, et al:
Electroencephalogr Clin Neurophysiol 60:183-196, 1985; Lombroso CT: In
Wasterlain CG, Treeman DM, Porter R, editors: Advances in neurology, New
York, 1983, Raven Press; and includes both full-term and premature infants.
†Burst-suppression pattern, marked voltage suppression, and electrocerebral
Silence.
‡Voltage asymmetries and “immaturity.”
Causes of Neonatal Seizures and
Outcomes
Cause
Hypoxic-ischemic encephalopathy
Intraventricular hemorrhage
Subarachnoid hemorrhage
Hypocalcemia
Early-onset
Later-onset
Hypoglycemia
Bacterial meningitis
Developmental malformations
Benign familial neonatal convulsions
Fifth-day fits
Percent of
Patients Who
Have Normal
Development
50
10
90
50
100
50
50
0
~100
~100
Complications





Cerebral palsy
Hydrocephalus
Epilepsy
Spasticity
Feeding difficulties
Consultations

Neurology consult needed for
- evaluation of seizures
- evaluation of EEG and video EEG
monitoring
- management of anticonvulsant
medications
Further Outpatient Care

Neurology outpatient evaluation
 Developmental evaluation for early
identification of physical or cognitive deficits
 Orthopedic evaluations if with joint
deformities
 Consider physical medicine/physical therapy
referral if indicated
References
1.Volpe JJ.Neonatal seizures. In:Neurology of the newborn.4th
ed.Philadelphia,Pa:WB Saunders's Co;2001:178-214
2.Hahn J,Olson D.Etiology of neonatal
seizures.NeoReviews.2004;5:327-335
3.Riviello,J.Drug therapy for neonatal seizures:Part
I.NeoReviews.2004;5:215-220
4.Riviello,J.Drug therapy for neonatal seizures:Part
II.NeoReviews.2004;5:262-268
5.Fanaroff A,Martin R,Neonatal seizures.In:Neonatal-Perinatal
Medicine-Diseases of the fetus and infant.6th
ed.St.Louis,MO:Mosby-Yearbook Inc.1997:899-911
6.Sheth R, Neonatal seizures;Emedicine.com
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