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NEONATAL SEIZURES

AMMAR KATERJI, MD

HOPE CHILDREN HOSPITAL

Definition

A paroxysmal alteration in neurological

function (behavior, motor, and/or

autonomic function) results from an

excessive synchronous electrical

discharge( depolarization ) of neurons

within the CNS

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 41,000 infants)

Why do neonatal seizures have

such unusual presentations?

Immature CNS cannot sustain a

synchronized, well orchestrated

generalized seizure

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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 NMDA receptors

and AMPA receptors overexpressed.

Deficient development of substantia nigra system for

inhibition of seizures.

Impaired propagation of electrical seizures, and

synchronous discharges.

Volpe JJ.Neonatal Seizures.In:Neurology of the Newborn.4th ed.

Probable Mechanisms of Some Neonatal Seizures

PROBABLE MECHANISM DISORDER

Failure of Na + -K + pump secondary to Hypoxemia, ischemia,

adenosine triphosphate and hypoglycemia

Excess of excitatory neurotransmitter

(eg.glutamic acid—excessive excitation) Hypoxemia, ischemia

and hypoglycemia

Deficit of inhibitory neurotransmitter Pyridoxine dependency

(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

Epileptic

Non-epileptic

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)

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Jitteriness Versus Seizure

CLINICAL FEATURE JITTERINESS SEIZURE

Abnormality of gaze or eye O +

movement

Movements exquisitely stimulus + O

sensitive

Predominant movement Tremor Clonic jerking

( rhythmic, equal rate amplitude) (fast and slow)

Movements cease with passive + O

flexion

Autonomic changes O +

tachycardia, apnea, increase blood pressure

pupillary change, salivation. ------------------------------------------------------------------------------------------------------------------

Classification of Neonatal

Seizures

Clinical

Electroencephalographic

Classification

Clinical Seizure

Subtle

Tonic

Focal, Generalized

Clonic

Focal, Multifocal

Myoclonic

Focal, Multifocal, Generalized

Clinical Classification

1. Subtle More in preterm than in term

Eye deviation (term)

Blinking, fixed stare (preterm)

Repetitive mouth and tongue movements

Apnea, autonomic phenomena

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

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Clinical Classification

4. Myoclonic

Rare

Focal, multifocal or generalized

Lightning-like jerks of extremities

(upper > lower)

Classification of Neonatal Seizures

ELECTROENCEPHALOGRAPHIC SEIZURE

CLINICAL SEIZURE COMMON UNCOMMON

Subtle +*

Clonic

Focal +

Multifocal +

Tonic

Focal +

Generalized +

Myoclonic

Focal, multifocal +

Generalized +

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*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 surface-

recorded EEG or inconsistently propagated to

the surface.

Most common is generalized tonic. Focal,

multifocal myoclonic, certain subtle seizures

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

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Etiology

Pregnancy history

Infections, fetal distress, preeclampsia

Delivery history

Type of delivery, any events during delivery

Postnatal history

Temperature, blood pressure, feeding,

Etiology

1- Hypoxic-Ischemic Encephalopathy

Single most common cause 20%

60% the onset within 12 hours

2- Intracranial hemorrhage

15% of term and 30% of preterm infant

3- Primary subarachnoid hemorrhage

Usually on the second postnatal day

Well baby with seizures

Etiology

4- Subdural Hemorrhage

5- Neonatal stroke

6- Intracranial infection

5-10%, bacterial meningitis group B, E coli

viral encephalitis TORCH

7- Developmental defects

8- Metabolic disturbances

Hypglycemia, hypocalcemia, disturbance of

AA and OA, local anesthetic intoxication

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

Etiology

9- Genetics

Tuberous sclerosis

Incontinenta pigmenti

Zellweger syndrome

Smith-Lemli-Opitz syndrome

Neonatal Adrenoleukodystrophy

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Etiology

10- Epileptic Syndromes

Benign familial neonatal seizures

Benign idiopathic neonatal seizures

( Fifth-day fits )

Early myoclonic encephalopathy

Early infantile epileptic encephalopathy

( Ohtahara syndrome )

0 10 20 30 40 50

Hypoxia-ischemia

Hemorrhage

Trauma

Stroke

Meningitis

Hypocalcemia

Hypoglycemia

Malformation

Incidence (%)

1970

1987

Comparison of prominent etiologic diagnoses of

seizures in the newborn period. (Data modified

from Mizrahi and Kellaway, 1987; Rose and

Lombroso, 1970)

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

TIME OF ONSET* RELATIVE FREQUENCY†

0-3 DAYS >3DAYS PREMATURE FULL TERM

Hypoxic-ischemic + +++ +++

encephalopathy

Intracranial + + ++ +

hemorrhage‡

Intracranial infection + + ++ ++

Developmental + + ++ ++

defects

Hypoglycemia + + +

Hypocalcaemia + + + +

Other metabolic + +

Epileptic syndromes + + +

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

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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, pyruvate, reducing substance.)

Blood and urine toxic screen

Blood and urine amino and organic acid screen

CT, MRI 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

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)

Treatment

Identify the underlying cause:

hypoglycemia - D10 solution

hypocalcemia - Calcium gluconate

hypomagnesemia- Magnesium sulfate

pyridoxine deficiency- Pyridoxine

meningitis- initiation of antibiotics

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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

Acute therapy of neonatal seizures

If with hypoglycemia- Glucose 10%: 2ml/kg IV

If no hypoglycemia- Phenobarbital:20mg/kg IV

loading dose, over 10-15 minutes

If necessary : additional Phenobarbital:

5 mg/kg IV to a max of 20 mg/kg

to achieve concentration 40-50µg/ml

Fosphenytoin: 20 mg/kg, IV (1 mg/kg/min)

Lorazepam:0.05-0.10 mg/kg, IV (half life 48hrs)

or Midazolam 0.15mg/kg bolus followed by

infusion 0.4mg/kg/h, max 1.1mg/kg/h

Expected Response of Neonatal Clinical

seizures to sequence of Therapy

Anticonvulsant Drug Cessation of Seizure

Phenobarbital 20mg/kg 40%

Phenobarbital 40mg/kg 70%

Phenytoin 20mg/kg 85%

Lorazepam 0.05-0.1 mg/kg 95%

Response of Neonatal Electrographic

Seizures to Phenobarbital and Phenytoin

Extent of Control

Complete ≥80% Reduction

Phenobarbital 43%

plus phenytoin 57% 80%

Phenytoin 45%

plus phenobarbital 62% 72%

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

Drug Therapy For Neonatal Seizures Standard Therapy

AED Initial Dose Maintenance Dose Route

Phenobarbital 20mg/kg 3 to 4 mg/kg per day lV, lM, PO

Phenytoin 20 mg/kg 3 to 4 mg/kg per day lV, POª

Fosphenytoin 20 mg/kg phenytoin 3 to 4 mg/kg per day lV, lM

equivalents

Lorazepam² 0.05 to 0.1 mg/kg Every 8 to 12 hours lV

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.

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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

Levetiracetam 20-60 mg/kg/d bid or tid

Lidocaine: 2 mg/kg, up to 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

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

Determinants of Duration of

anticonvulsant therapy for neonatal

seizures

Neonatal neurological examination

Cause of neonatal seizure

Electroencephalogram

Duration of anticonvulsant therapy-

Guidelines

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 therapy-

Guidelines

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

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Prognosis of Neonatal seizures in relation

to EEG

EEG BACKGROUND NEUROLOGICAL SEQUELAE(%)

Normal 10

Severe abnormalities† 90

Moderate abnormalities‡ ~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.”

Prognosis of Neonatal Seizures

Relation to Maturity

Maturity Normal Dead Sequelae

Term ≥2500 g 60% 10% 30%

Pemature ≤2500 g 35% 35% 30%

Premature ≤1500 g 20% 40% 40%

Causes of Neonatal Seizures and Outcomes

Percent of

Patients Who

Have Normal

Cause Development

Hypoxic-ischemic encephalopathy 50

Intraventricular hemorrhage 10

Subarachnoid hemorrhage 90

Hypocalcemia

Early-onset 50

Later-onset 100

Hypoglycemia 50

Bacterial meningitis 50

Developmental malformations 0

Benign familial neonatal convulsions ~100

Fifth-day fits ~100

Complications

Cerebral palsy

Hydrocephalus

Epilepsy

Learning disability, mental retardation

Feeding difficulties

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;2008: 203-237

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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