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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

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Neonatal seizures l.jpg

NEONATAL SEIZURES

Maria Theresa M. Villanos, MD

PL-2


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Definition

  • A stereotypic, paroxysmal spell of altered neurologic function

    (behavior, motor,and/or autonomic function)


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Definition

  • Neonatal period limited to :

    - first 28 days for term infants

    - 44 weeks gestational age for

    pre-term


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Frequency

  • In US – incidence has not been established clearly

  • Estimated frequency of 80-120 per 100,000 neonates/year

  • 1-5:1000 live births


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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


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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.


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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.


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Probable Mechanisms of Some Neonatal Seizures

PROBABLE MECHANISMDISORDER

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.


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Classification of Neonatal Seizures

  • Clinical

  • Electroencephalographic


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Classification

I. Clinical Seizure

  • Subtle

  • Tonic

  • Clonic

  • Myoclonic


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Classification

II. Electroencephalographic seizure

  • Epileptic

  • Non-epileptic


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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


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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


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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)


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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


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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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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.


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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


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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


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Jitteriness Versus Seizure

CLINICAL FEATUREJITTERINESSSEIZURE

Abnormality of gaze or eye O +

movement

Movements exquisitely stimulus + O

sensitive

Predominant movement Tremor Clonic jerking

Movements cease with passive + O

flexion

Autonomic changes O +

------------------------------------------------------------------------------------------------------------------


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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.


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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


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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.


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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 is important

  • Search for history that supports TORCH infections

  • History of fetal distress, preeclampsia or maternal infections


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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


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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


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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.


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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 + + +


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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)


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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


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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, FECl³, reducing substance.)

Blood and urine toxic screen

Blood and urine amino and organic acid screen

CT or ultrasound scan


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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


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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


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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


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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

Diazepam²´ 0.25 mg/kg Every 6 to 8 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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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


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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


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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

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)


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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


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Determinants of Duration of anticonvulsant therapy for neonatal seizures

  • Neonatal neurological examination

  • Cause of neonatal seizure

  • Electroencephalogram


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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


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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


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Prognosis

Two most useful approaches in utilizing outcome

  • EEG

  • Recognition of the underlying neurological disease


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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 in relation to EEG


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Causes of Neonatal Seizures and Outcomes

Percent of

Patients Who

Have Normal

CauseDevelopment

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


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Complications

  • Cerebral palsy

  • Hydrocephalus

  • Epilepsy

  • Spasticity

  • Feeding difficulties


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Consultations

  • Neurology consult needed for

    - evaluation of seizures

    - evaluation of EEG and video EEG

    monitoring

    - management of anticonvulsant

    medications


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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


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References

1.Volpe JJ.Neonatal seizures. In:Neurology of the newborn.4thed.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-PerinatalMedicine-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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