NEONATAL SEIZURES Maria Theresa M. Villanos, MD PL-2.

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


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


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


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


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)


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


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

Thank You

NEONATAL SEIZURES Maria Theresa M. Villanos, MD PL-2.

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