NEONATAL SEIZURES

1
NEONATAL SEIZURES

• Maria Theresa M. Villanos, MD
• PL-2

2
Definition

• A stereotypic, paroxysmal spell of altered
  neurologic function
• (behavior, motor,and/or autonomic function)

3
Definition

• Neonatal period limited to
• - first 28 days for term infants
• - 44 weeks gestational age for
• pre-term

4
Frequency

• In US incidence has not been established
  clearly
• Estimated frequency of 80-120 per 100,000
  neonates/year
• 1-51000 live births

5
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

6
Why do neonatal seizures have such unusual
presentations?

• Immature CNS cannot sustain a
  synchronized, well orchestrated generalized
  seizure

7

• Perinatal Anatomical and Physiological Features
  of Importance in Determining Neonatal Seizure
  Phenomena
• ANATOMICAL
• Neurite outgrowthdendritic and axonal
  ramificationsin
• process
• Synaptogenesis not complete
• Deficient myelination in cortical efferent
  systems

Volpe JJ.Neonatal Seizures Neurology
of the Newborn.4th ed.
8

• Perinatal Anatomical and Physiological Features
• of Importance in Determining Neonatal Seizure
  Phenomena
• PHYSIOLOGICAL
• In limbic and neocortical regionsexcitatory
  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.InNeurology of the
Newborn.4th ed.
9

• 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 acidexcessive 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 SeizuresNeurology 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

15
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 gt 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

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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

21
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

22

• Jitteriness Versus Seizure
• CLINICAL FEATURE JITTERINESS SEIZURE
• 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 jerkingcharacteristic of
  subtle seizure
• Sucking, puckering movements not accompanied by
  ocular fixation or deviation
• SLEEP
• Fragmentary myoclonic jerksmay be multiple
• Isolated, generalized myoclonic jerk as infant
  wakes from sleep

Volpe JJ.Neonatal SeizuresNeurology of the
Newborn.4th ed.
24
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

27
Etiology

• Pregnancy history is important
• Search for history that supports TORCH infections
• History of fetal distress, preeclampsia or
  maternal infections

28
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

30

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.
InNeonatal and Perinatal Medicine, Diseases of
the Fetus and Infant,6th ed.
31

• Major Etiologies of Neonatal Seizures in Relation
  to Time of
• Seizure Onset and Relative Frequency
• 
  TIME OF ONSET RELATIVE FREQUENCY
• 0-3 DAYS gt3DAYS
  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
37

• 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)

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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- Phenobarbital20mg/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)
• Lorazepam0.05-0.10 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 newbornfree 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 gt30 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
45
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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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 60183-196,
  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.

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• 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

51
Complications

• Cerebral palsy
• Hydrocephalus
• Epilepsy
• Spasticity
• Feeding difficulties

52
Consultations

• Neurology consult needed for
• - evaluation of seizures
• - evaluation of EEG and video EEG
• monitoring
• - management of anticonvulsant
• medications

53
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

54
References

• 1.Volpe JJ.Neonatal seizures. InNeurology of the
  newborn.4th ed.Philadelphia,PaWB Saunders's
  Co2001178-214
• 2.Hahn J,Olson D.Etiology of neonatal
  seizures.NeoReviews.20045327-335
• 3.Riviello,J.Drug therapy for neonatal
  seizuresPart I.NeoReviews.20045215-220
• 4.Riviello,J.Drug therapy for neonatal
  seizuresPart II.NeoReviews.20045262-268
• 5.Fanaroff A,Martin R,Neonatal seizures.InNeonata
  l-Perinatal Medicine-Diseases of the fetus and
  infant.6th ed.St.Louis,MOMosby-Yearbook
  Inc.1997899-911
• 6.Sheth R, Neonatal seizuresEmedicine.com

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Thank You