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Definition

Neonatal seizures • Seizures in the first 28 days of life of a FT

Jorge Vidaurre, M.D. • Seizures limited to the period of 44 weeks

Department of Pediatric Neurology of conceptional age (CA), defined as the
chronological and gestational age

Incidence between 1.8-5.1/ 10000 live births

Incidence of seizures is greater in neonatal period than What factors play a role in the
any other time in life.
increased incidence of seizures in
the neonatal period ?
33% of neonates with seizures can be diagnosed as SE,
using definitions of 30 min. seizures or recorded Sz. in
at least 50% of the recording.

It is believed that period of enhanced epileptogenesis is

at 34 weeks of GA.

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The perinatal period is one of rapid brain growth,

and possibly a mayor number of synapses.

Increase excitation
Abundance of excitatory synapses, high density of
receptors for excitatory neurotransmitters.

Decrease inhibition Inhibitory neurotransmitters (GABA) are excitatory

in newborns, substancia nigra may amplify this effect

Accumulation of extra cellular K+,

GABA exitation
increasing excitation.
Glut/exitation

Weak surrounding inhibition.

Perinatal period is relatively hostile.

GDP’s
GABA/inhibition

10 15

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• The majority of seizures occur as acute,

reactive events in association with a wide Neonatal seizure classification
range of etiologic factors.
and pathophysiology
• There are a few distinct neonatal epileptic
syndromes with good or catastrophic
prognosis

 There have been a series of efforts to classify neonatal seizures.

Electrographic seizure Electroclinical seizures
Each classification emphasizes the clinical features. Clinical “seizures”

 During the past decades the pathophysiology of these clinical

events has been debated.

 Initially, all the clinical events were presumed to be epileptic in

origin.

 However EEG studies demonstrated that many of these events are

non-epileptic in nature

Clancy, 2006

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Early investigators described clinical manifestations

 Many infants have only electrographic seizures unique of newborns:
Oral-buccal-lingual automatisms
 Consequently without EEG monitoring is
Limb movements progressions
extremely difficult to quantify seizures.
(Minkowki ans Sainte-Anne Daragassies,1956; Rose and Lombroso, 1970,
Volpe ,1973; Mizrahi and Kellaway, 1987)
 Many abnormal, paroxysmal attacks manifested in
the sick neonate do not show an electrographic
correlate. They recognized the absence of GTC seizures.

EEG studies demonstrated that many of those clinical

manifestations are non-epileptic in nature.

Classification based on clinical characteristics • Sustained posturing of

and pathophysiology. single limbs
• Sustained
• Repetitive rhythmic contractions of
muscle groups. • Focal tonic asymmetrical posture
• Occurring Synchronously or
of trunk.
Focal clonic
asynchronously on one side or • Sustained eye
simultaneously but asynchronous on deviation
both sides
• Can not be provoked or
• Unifocal or multifocal
suppressed.
• Can not be suppressed by restrain.
• Pathophysiology:
• Pathophysiology: Epileptic
Epileptic.

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

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• Sustained symmetrical • Random, single, brief

posturing of limbs, trunk,and contractions of muscle
neck groups.
• May be flexor, extensor or • Typically not repetitive or
mixed. may recur at slow rate.
• Generalized tonic • Myoclonic
• May be provoked or • May be generalized, focal or
suppressed. fragmentary.
• Presumed pathophysiology: • May be provoked by
Nonepileptic stimulation.
• Pathophysiology: Epileptic
or Nonepileptic

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

• Random and roving eye

• May be flexor, extensor, or
movements or nystagmus
mixed
• Motor automatisms, • May be provoked or
• Spasms • May occur in clusters ocular signs suppressed
• Can not be provoked or
• Presumed
suppressed
pathophysiology: Non-
• Pathophysiology: Epileptic epileptic

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

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• Rowing or swimming
• Sucking,chewing,tongue movements
protrusions • Pedaling or bicycling
• May be provoked or movements of legs
• Oral-buccal-lingual suppressed Progression movements • May be provoked or
movements
• Presumed pathophysiology: suppressed
Non- epileptic • Presumed
pathophysiology: Non
epileptic

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

• Sudden arousal with

increased random activity
• Complex purposeless of limbs
movements • May be provoked or Electroencephalography of the
suppressed neonate with seizures
• Presumed
patho[physiology: non
epileptic

Mizrahi and Kellaway 1998; Mizrahi and Clancy 2000

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Routine EEG
 Can be performed in the EEG lab or the hostile environment
of NICU

 Need of knowledgeable, experienced technologist

 Need of specially trained electroencephalographer who is

familiar with neonatal EEG.

 Advantage: “snapshot” of background EEG and transient

patterns and it‟s prognostically helpful. (Holmes and Lombroso,1993,
Watanabe,et al 1999)

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Developmental progression of discontinuity

• Conceptional age Behavioral State

• Awake Active Quiet

sleep
sleep

• <29

• 30

• 32

• 36

• 40

• 44

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Interictal EEG
• Background activity can give valuable information about state of
development, CA and determination of a prognosis

FP3 FP4
• The more abnormal the background activity the more likely that
FZ
seizures occur.

T3 C3 Cz C4 T4 • Very abnormal background (Flat EEG‟s or burst suppression pattern)

is predictive of adverse outcome including death and chronic static
encephalopathies
PZ
O1 O2
• Focal sharp waves are not considered an interictal epileptiform
activity

• Some findings suggest structural changes, like positive rolandic sharp

waves suggesting IVH or PVL and independent B/L multifocal sharps
can indicate diffuse dysfunction

Abnormal interictal EEG

• Normal
• Undifferentiated
• Depressed
• Depressed and undifferentiated
• Suppression-burst pattern
• Isoelectric

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 The presence of marked background abnormalities severe

cerebral dysfunction, predicting future electrographic
seizures.

 A study evaluating high risk neonates, such as HIE with

abnormal background showed that 81% subsequently
displayed electrographic seizures vs 4 % of the neonates
with normal or immature background. (Laroia et al,1984)

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Electrographic neonatal seizure

Long term monitoring????
(ENS)
 Goal: detect the presence and burden of electrographic • Arbitrary definition of rhythmic activity of at least
seizures 10 seconds in duration

 Snapshot EEG of 30 minutes may miss electrographic

seizure that are not so frequent. • An electrographic seizure is a discrete event with
definable beginning, middle and end.

 If seizures are more likely to occur in high risk neonates • A fundamental observation: ENS essentially
(HIE), should we monitor them????? always arise focally

•They can be multifocal, can occur in different brain Typical duration of ENS is about 2-3 min, most are
region, most often asynchronous relatively brief

•Location usually midtemporal (T3-T4) or central Dramatic variability in wave forms and frequency,
seizures can differ from one to the next in same baby

•Focality does not convey localizing information

80% of ENS can occur without clinical manifestations

•ENS can migrate to different regions, some display

the interesting phenomena of been simultaneous but It is possible that clinical seizures are just the tip of the
independent iceberg

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The natural history of ENS is that they are brief and After AED use clinical seizures stop first but
recurrent, it is common to see an initial burst of ENS can persist.
seizures in the first 2-3 days, then disappear
gradually in the next week.

One quarter to one third of neonates with seizures

ENS are very resistant to AED treatment
represent neonatal status epilepticus (orbitus,1996).

Proposed definition of neonatal status epilepticus: >

50% of EEG record was occupied by ENS.

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Etiology
Most neonatal seizures are acute and reactive to a CNS insult

• Hypoxic-ischemic encephalopathy
Intracranial hemorrhage (IVH, ICH,SDH,SAH)
• Infection (intrauterine, meningitis, encephalitis)
• Infarction
• Metabolic(Hypoglycemia,hypocalcemia-magnesemia)
• Cerebral dysgenesis and chromosomal abnorm.
• Neurodegenerative disorders and inborn errors of
metabolism

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General considerations
• Are neonatal seizures an innocent phenomena and just a
marker of severe brain dysfunction or may they amplify
the neurological damage caused by the precipitating
etiology??
• Despite vigorous debate, this issue has not been resolved
(mizrahi,1999; Holmes,1997; Jensen,1999)
12/30/2012
Treatment of neonatal seizures
 Studies have indicated that the occurrence of electrographic
seizures is associated with high morbidity and mortality (Connell
et al, 1989; Mc Bride et al, 2000).
 These Electrographic seizures have been correlated with
microcephaly, CP and risk of dying.
 Even if studies have compared neonates at risk with and without
ENS with similar APGAR scores and PH, it may be that neonates
with ENS have a more severe damage, represented by more
abnormal background in the EEG.
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Human evidence
 Seizures may induce autonomic changes usually
accompanying the motor phenomena. Apnea, tachycardia,
HTN, increased cerebral flow velocity, skin flushing.
 Depression of cerebral phosphocreatine to inorganic
phosphate ratios measured by MRS during and after ENS.,
consistent with metabolic depletion of high energy
metabolites (Youkin et al,1986; Clancy et al, 1988; Boylan et al,199).
This observations do not answer the question wether ENS damage the
brain
• Phenobarbital has been the traditional choice of neurologists
and neonatologists. Unfortunately there is no firm scientific
basis for this practice.
• No formal prospective, randomized, placebo-controled trial has
ever shown the efficacy of Phenobarbital.
• Effective in less than 50% of patients. A study randomizing
neonates with treatment either to phenobarbital or phenytoin
showed cessation of electrical seizures in 43% and 45% of both
groups respectively ( Painter et al 1999).
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Animal experiments
 Rat pups subjected to recurrent seizures had impaired
memory and learning behavior as adults, in addition to
lower threshold to seizures with pentylenetetrazol and
neuroplastic changes favoring epileptogenesis (sprouting
of mossy fibers in CA3 region). (Holmes et al,1998; Huang et
al,1999; Schmidt et al, 1999).
 Can we extrapolate the effects or early seizures in animals
to humans????
 The seizures in animals are primary hipoccampal in origin
 Seizures in animals are more sustained and recurrent
 One study showed that in 31 acutely ill, monitored
neonates with ENS, only 2 of them had complete cessation
of electro-clinical seizures, 6 had an equivocal
electroclinical response. Clinical cessation of seizures
occurred in 13 infants. Although the Electrographic
seizures continued (“uncoupling”) (Conell,et al 1989)
 Recent studies in immature rodents suggest that traditional
AED‟s like phenytoin, diazepam, valproate and
phenobarbital may produce widespread apoptosis of
neurons (Bittigau et al 2002).
 The only AMPA antagonist is topiramate and it‟s an
effective anticonvulsant and neuroprotector in a rat
perinatal hypoxia-induced seizure model ( Koh and
Jensen,2001; Koh et al, 2004)
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In a recent editorial in Neurology 2005: “ Neonatal seizures:
After all these years we still love what doesn’t work”, Sankar
and Painter wrote that the endurance of phenobarbital and
phenytoin in the treatment of neonatal seizures, likely rests in the
relative comfort of physicians with the safety and availability of
these drugs in parenteral forms, and not due to their “impressive
efficacy”
 Evans and Levine in their Cochrane review about the
treatment of neonatal seizures stated “ at the present time
anticonvulsant therapy administered in the immediate
period following perinatal asphyxia can not be
recommended for routine clinical practice”, other than in
the treatment of prolonged, or frequent seizures” (Evans and
Levine 2001)
12/30/2012
A randomized prospective study about neuroprotection in term
infants with severe asphyxia showed that:
phenobarbital at 40mg/kg was safe and associated with a 27%
reduction in the incidence of seizures in comparison with the
control group ( 9/15 neonates in the Pb group and 14/16 in the
control group). Sample size was calculated to detect 50%
reduction in the incidence of seizures, so Pb showed an
insignificantly lower occurrence of seizures.
Nevertheless, the Pb group performed better on
neurodevelopmental follow up at 3 years ( Normal neurologic
outcome in 11/15 in the Pb group and 3/16 in the control
group). (Hall et al 1998).
that Pb has a protective effect decreasing the rate of
Some believe
brain metabolism( Nilsson,1971; Donegan,1985).
What options do we have in the setting of
refractory status given the lack of efficacy of the
traditional AED‟s?
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Midazolam

 A recent study addressed the efficacy of Midazolam in treating neonatal seizures.

 The investigators demonstrated complete electrographic control in 13 non-responder to
phenobarbital and phenytoin, when midazolam was administered within an hour of
General considerations
failure to traditional AED‟s.
• They encountered no adverse reactions.

 86.7 % of patients that responded to conventional therapy had a normal neurological

• There is no clear evidence of the effect of seizures
outcome
in the developing brain.
 11.8% of the non-responder to phenyytoin/phenobarbital had normal developmental
outcome.

 53.9% of the 13 patients treated with midazolam had a normal neurodevelopmental

outcome
• There is no definite evidence of the effect of AED
 Limitations of the study:
 Retrospective and not randomized. in the human brain.
 Midazolam was not compared to phenobarbital or phenytoin.
 Over the period studied NICU care independently of midazolam may have had a
positive impact improving outcome.

 Midazolam a GABA agonist still raises concern about potential neurotoxicity.

(Castro Conde et al 2005)

Consider frequency and duration of seizures

• The old clinical adage “treat the patient not the EEG” is
outdated in the treatment of neonates.
Some seizures would not respond to AED if
etiology is not addressed.
• If the gold standard is the total elimination of ENS, then
the EEG serves as the gold standard not only to establish
the presence of seizures, but also to demonstrate the
Is there a clear end-point when using AED??? efficacy of the treatment.
Should we eliminate the clinical seizures???
Should we try to stop electrographic seizures???

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Etiology- specific Therapy Etiology- specific therapy

• Glucose 10% Solution • 2ml/kg IV in acute • Magnesium sulfate, • .25ml/kg IM can be
phase, to 8 mg/kg min. 50% sol. repeated every 12 hrs.
of maintenance.

• Pyridoxine • 100mg IV
• Calcium gluconate,10% • 2ml/kg IV over 10
solution min. acutely then
8ml/kg/day

AED therapy Some studies are proving that phosphenytoin is safe

in neonates and is comparable to metabolism in older
children.
• The first line AED are Phenobarbital, phenitoin,
benzodiazepine (diazepam or Lorazepam ) Acute administration of AEDs carry the risk of
• Phenobarbital is almost universally accepted as adverse reactions:
first line and phenytoin second line AED CNS depression
• Painter et al compared the effectiveness of Pb vs.
PHT in seizure control and neither proved so Hypotension
efficacious as generally believed (maximum efficacy Bradycardioa
no grater than 38%), specially preventing recurrence
in severe seizures. Respiratory depression
Cardiac arrhythmia

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Approach of neonatal Sz. Based on

Other adjuvant AEDs have been used but trials have
not been controlled, involving infants that already clinical observations
failed first line AEDs or who were receiving other • Focal clonic or focal tonic • Aggressive AEDs
AEDs prolonged and recurrent
When starting AED, some considerations should be
made:
Not all neonatal seizures require AED such as: • Focal clonic or focal tonic • AEDs???, use of drugs can
brief and infrequent have more risks than brief
-Seizures of non-epileptic origin
and infrequent seizures.
-Brief, infrequent epileptic seizures???

• Generalized tonic and • No AEDs

motor automatisms (subtle Clinical seizures in the absence of EEG ( motor
seizures) intensified by
automatisms and generalized tonic) do not require
stimuli and suppressed by
treatment with AEDs
restraint

• Generalized tonic and • Some clinicians may

motor automatisms not
responsive to stimulation or
restraint
• EEG is a very valuable tool
EEG seizure activity without clinical seizures
withhold AEDs considering
(paralyzed neonates, with encephalopathy, or neonates
that clinical features are
receiving AEDs) are highly resistant to AEDs many
enough support of non-
times polypharmacy is needed and serious adverse
epileptic origin, some may
effects can complicate clinical pictures
start AEDs, due to lack of
response to stimuli.

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Acute therapy First- line AED therapy

• Balanced AED regimen to minimize adverse • Diazepam • .25mg/IV,bolus Half life 31-54h
events and maximize therapeutic effectiveness may be repeated
.5mg/kg rectal
• Acute therapy is initiated with phenobarbital to
eliminate clinical seizures
• Lorazepam • .05mg/kgIV Half life 31-54h
may be repeated
• If clinical seizures persist Pb dose may be
increased, then if necessary PHT is added. If
required a benzodiazepine may be used.

First-line AED therapy Second-line IV AED therapy

• Phenobarbital • 20-40mg/kg IV,bolus Half life 100h • Clonazepam • 0.1 mg/kg IV level: 28-117 mg/ml
3-4 mg/kg maintenance after day 5-7 over 5 „ Higher doses may be < effect

• Lidocaine • 4mg/kg/hr, 1 day Levels 2.8-10.5 mg/l

• Phenytoin • 20mg/kg over 30‟ Half life 100h or2mg/kg, with Narrow TX. range
3-4mg/kg in 2-4 doses ( 40-200) reduction of 1mg/kg Higher doses can be
for maintenance on subsequent days. A convulsant

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Second-line IV AED therapy
• Midazolam • 0.15mg/kg bolus Water soluble, without
0.1-.4mg/kg/h/IV polyethylene glycol
• Paraldehyde • 400-200mg/kg/IV Levels >10, clearance
200mg/kg IV or decreased by Pb and
16mg/kg/h asphyxia
Second line P.O AED therapy
• Primidone 15-25mg/kg loading Elevation of PB level
12-20mg/kg maintenance if given concurrently
Levels 3-18mug/l
Difficult Achieving
initial high levels
• Vigabatrin 50mg/kg P.O/d Incomplete data in
neonates, greater
experience in infantile
spasms
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Second-line oral AED therapy
• Carbamazepine 5mg/kg q 12h Investigated as
alternative maintenance
No data on efficacy
20-26mg/kg P.O. Used associated with
• Valproate 5-10mg/kg q 12h hyperammonemia, caution
maintenance in polytherapy
Acute therapy
• If clinical seizures are controlled but EEG seizures
persist, PB and PHT are increased to maximize
serum levels. If failure to conventional treatment
midazolam is a consideration.
• If with high therapeutic levels EEG seizure control
is not achieved it is likely that further therapy may
provide only the potential for CNS depression
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Chronic therapy Chronic therapy

• Not all neonates need chronic therapy for the • The discontinuation of AEDs after clinical
treatment of the acute seizures seizures is individualized

• There have been increasing interest in using a

• Levels of AEDs can be difficult to control, short term regimen with withdrawal of AEDs 2
requiring lower doses in the first weeks, that can weeks after the last clinical seizure and evaluation
lead to accumulation and toxicity and higher doses of the EEG for the presence of electrographic
after this period seizures before discontinuation of medications

Prognosis
• Few comprehensive studies delineate a There is general consensus that the
relationship between cessation of seizures and
outcome primary factor predicting outcome is
the etiology or underlying cause
• Easily controlled seizures may be the result of precipitating the epileptic event
transient or benign CNS disorders

• Refractory seizures can be the result of more

severe brain disorders

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Factors affecting prognosis
• Interictal EEG
• Serial recordings
• Neurologic exam and changes over time
• Findings in neuroimaging
• The character and duration of seizures?
• CA and birth weight?
• All variables relate to 1 single factor, the degree of
brain injury and this relate to etiology
Predictors of post neonatal epilepsy
(PNE) R Clancy and A. Legido, Epilepsia,1991
• Incidence of epilepsy as high as 56% in children
with seizures in the neonatal period. The most
important clinical parameter relate to PNE was
neonatal clinical-neurologic evaluation. CA with
birth weight did not reached statistical significance
• EEG parameters important in predicting PNE were
interictal background and number of seizures/hr
(>10), but not the seizure duration or % of EEG
seizure activity
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Studies have demonstrated favorable outcome in
30% of survivors
Unfavorable outcome in 70%
Mortality as high as 33% ( studies can be bias because this
studies had been performed in centers with sicker neonates)
Post neonatal epilepsy 20-56% (variability depends on the
use of EEG, the highest incidence found in neonates with EEG
correlation of their clinical seizures in a tertiary center with sicker
neonates) (Ellenberg, 1984; Sher et al,1993; Clancy and Legido,1991)
MR in survivors 67%
CP in survivors 63% (consideration has to be made that
incidence of MR and CP has been taken from studies in a tertiary center)
Patients with persistent clinical deficits such as MR
or CP the rate of PNE was significantly higher >
86%
When patients developed PNE they do so usually in
the first year and they develop different types of
seizures including infantile spasms and minor motor
seizures which usually do not respond to
phenobarbital, so 60% of patients developed
seizures while on treatment
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What about the future?

Most neonatal seizures occur as a non-specific
sign of acute brain injury, if event is powerful
enough to cause encephalopathy ( coma,
hypotonia) and markedly abnormal EEG
background, the stage is set for a chronic non-
progressive encephalopathy with MR, CP and
PNE
• Neurology Group on neonatal seizures has been formed to
create multicenter randomized placebo controlled trials
evaluating efficacy of phenobarbital ( Clancy R. Summary
Proceedings From the Neurology group on Neonatal seizures
Pediatrics 2007)
• New ways of continuous EEG monitoring (a EEG)

Basic Research
• Bumetanide increased the efficacy of phenobarbital in rats,
probably shifting the Cl- currents
GABA

Cl- Bumetanide

Cl- cotransport

Questions??

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