neonatal seizures maria theresa m. villanos, md pl-2
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NEONATAL SEIZURESNEONATAL SEIZURES
Maria Theresa M. Villanos, MD
PL-2
DefinitionDefinition
A stereotypic, paroxysmal spell of altered neurologic function
(behavior, motor,and/or autonomic function)
DefinitionDefinition
Neonatal period limited to :
- first 28 days for term infants
- 44 weeks gestational age for
pre-term
FrequencyFrequency
In US – incidence has not been established clearly
Estimated frequency of 80-120 per 100,000 neonates/year
1-5:1000 live births
FrequencyFrequency
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 Why do neonatal seizures have such unusual presentations?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
PHYSIOLOGICALIn 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 DISORDER
Failure of Na + -K + pump secondary to Hypoxemia, ischemia, adenosine triphosphate and hypoglycemiaExcess of excitatory neurotransmitter (eg.glutamic acid—excessive excitation) Hypoxemia, ischemia and hypoglycemiaDeficit 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 of Neonatal Classification of Neonatal SeizuresSeizures
Clinical
Electroencephalographic
Classification Classification
I. Clinical Seizure Subtle Tonic Clonic Myoclonic
ClassificationClassification
II. Electroencephalographic seizure
Epileptic
Non-epileptic
Clinical ClassificationClinical 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 ClassificationClinical 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 ClassificationClinical 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 ClassificationClinical Classification
4. Myoclonic Rare Focal, multifocal or generalized Lightning-like jerks of extremities
(upper > lower)
Electroencephalographic seizureElectroencephalographic 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 Electroencephalographic seizuresseizures
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 Does absence of EEG seizure activity indicate that a clinical seizure activity indicate that a clinical seizure
is non- epileptic?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
Surface EEG-Silent SeizureSurface 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 JITTERINESS SEIZURE
Abnormality of gaze or eye O + movementMovements exquisitely stimulus + O sensitivePredominant movement Tremor Clonic jerking
Movements cease with passive + O flexionAutonomic changes O +------------------------------------------------------------------------------------------------------------------
Normal Neonatal Motor Activity Commonly Mistaken for Seizure
ActivityAWAKE OR DROWSYRoving, 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
SLEEPFragmentary myoclonic jerks—may be multipleIsolated, generalized myoclonic jerk as infant wakes from sleep
Volpe JJ.Neonatal Seizures:Neurology of the Newborn.4th ed.
EtiologyEtiology
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
EtiologyEtiology
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.
EtiologyEtiology
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
EtiologyEtiology
Pregnancy history is important Search for history that supports TORCH
infections History of fetal distress, preeclampsia or
maternal infections
EtiologyEtiology
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
EtiologyEtiology
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
0 10 20 30 40 50
Hypoxia-ischemia
Hemorrhage
Trauma
Stroke
Meningitis
Hypocalcemia
Hypoglycemia
Malformation
Incidence (%)
19701987
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,6 th 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
TERMHypoxic-ischemic + +++ +++ encephalopathyIntracranial + + ++ + hemorrhage‡Intracranial infection + + ++ ++Developmental + + ++ ++ defectsHypoglycemia + + +Hypocalcaemia + + + +Other metabolic + +Epileptic syndromes + + +
Inborn Errors of Metabolism Associated With Neonatal Seizures
Conditions That Have a Specific TreatmentPyridoxine (B6) dependencyFolinic acid-responsive seizuresGlucose transporter defectCreatine deficiency
Other ConditionsNonketotic hyperglycinemiaSulfite oxidase deficiencyMolybdenum cofactor deficiency (combined deficiency)Carbohydrate-deficient glycoprotein disorderLactic acid disordersMitochondrial disordersMaple syrup urine diseaseIsovaleric 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 Laboratory Studies to Evaluate Neonatal SeizuresNeonatal 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 Laboratory Studies to Evaluate Neonatal SeizuresNeonatal 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 specificsSerum
GlucoseElectrolytes (sodium, potassium, chloride, carbon dioxide), blood urea nitrogen, chromium, calcium, phosphorus, magnesiumUric acidCreative kinaseSerum ammoniaLactic and pyruvic acidsBiotinidaseAmino acidsSerum carnitine, acylcarnitinesSerum transferrinCopper and ceruloplasminCholesterolFatty 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
TreatmentTreatment
Identify the underlying cause:
hypoglycemia - D10 solution
hypocalcemia - Calcium gluconate
hypomagnesemia- Magnesium sulfate
pyridoxine deficiency- Pyridoxine
meningitis- initiation of antibiotics
TreatmentTreatment
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 RoutePhenobarbital 20mg/kg 3 to 4 mg/kg per day lV, lM,
POPhenytoin 20 mg/kg 3 to 4 mg/kg per day lV, POªFosphenytoin 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 lVDiazepam²´ 0.25 mg/kg Every 6 to 8 hours lV
AED= andtiepileptic drug; lV= intravenous; lM= intramuscular; PO= oralªOral phenytoin is not well absorbed.²Benzodiazepines typically not used for maintenance therapy.³Lorazepam preferred over diazepam.
Acute therapy of neonatal seizuresAcute 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 Pharmacological properties of
PhenobarbitalPhenobarbital 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 AEDsHigh-dose phenobarbital: >30 mg/kgPentobarbital: 10 mg/kg, then 1 mg/kg per hourThiopental: 10 mg/kg, then 2 to 4 mg/kg per hourMidazolam: 0.2 mg/kg, then 0.1 to 0.4 mg/kg per hourClonazepam: 0.1 mg/kgLidocaine: 2 mg/kg, then 6 mg/kg per hourValproic acid: 10 to 25 mg/kg, then 20 mg/kg per day in 3 dosesParaldehyde: 200 mg/kg, then 16 mg/kg per hourChlormethiazole: Initial infusion rate of 0.08 mg/kg per minuteDexamethasone: 0.6 to 2.8 mg/kgPyridoxine (B6): 50 to 100 mg, then 100 mg every 10 minutes (up to 500mg)
Alternative AEDs for Neonatal Seizures
Oral AEDsPrimidone: 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 Determinants of Duration of anticonvulsant therapy for neonatal anticonvulsant therapy for neonatal
seizuresseizures
Neonatal neurological examination
Cause of neonatal seizure
Electroencephalogram
Duration of anticonvulsant therapy-Duration of anticonvulsant therapy-GuidelinesGuidelines
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-Duration of anticonvulsant therapy-GuidelinesGuidelines
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
PrognosisPrognosis
Two most useful approaches in utilizing outcome
EEG
Recognition of the underlying neurological disease
Prognosis of Neonatal seizures in relation Prognosis of Neonatal seizures in relation
to EEGto EEG EEG BACKGROUND NEUROLOGICAL
SEQUELAE(%)
Normal 10
Severe abnormalities† 90Moderate abnormalities‡ ~50Based 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
Percent ofPatients WhoHave Normal
Cause DevelopmentHypoxic-ischemic encephalopathy 50Intraventricular hemorrhage 10Subarachnoid hemorrhage 90Hypocalcemia Early-onset 50 Later-onset 100Hypoglycemia 50Bacterial meningitis 50Developmental malformations 0Benign familial neonatal convulsions ~100Fifth-day fits ~100
ComplicationsComplications
Cerebral palsy Hydrocephalus Epilepsy Spasticity Feeding difficulties
ConsultationsConsultations
Neurology consult needed for
- evaluation of seizures
- evaluation of EEG and video EEG
monitoring
- management of anticonvulsant
medications
Further Outpatient CareFurther 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
ReferencesReferences
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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