APRIL 2006 VOLUME
3, NUMBER 8 In
this issue...
Concomitant with the increasing use of continuous
(a)EEG monitoring in the neonatal intensive care is
the awareness that subclinical seizures are very common
in neonates with clinical seizures, raising questions
about the effectiveness of anti-epileptic drugs in
neonates. These drugs were originally tested and used
in adults and older children; however, the immature
brain reacts differently to anti-epileptic drugs compared
to adult brains, and the seizure types can be very
diverse even within a patient. Further, both long-lasting
seizures as well as anti-epileptic drugs may have
adverse effects on the developing brain.
In this issue, we review recent research that raises
our clinical awareness of the dilemmas in these areas,
including the choice of anticonvulsant agents, the
incidence of epilepsy, and automated seizure detection. |
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Guest
Editors of the Month |
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Commentary
& Reviews:
Mona C. Toet
Neonatologist
Wilhelmina Children's Hospital, UMCU,
The Netherlands |
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Commentary
& Reviews:
Linda de Vries
Professor in Neonatal Neurology
Wilhelmina Children's Hospital, UMCU,
The Netherlands |
Guest Faculty Disclosure:
Mona C. Toet, MD
Faculty Disclosure: No relationship with commercial
supporters.
Linda de Vries, MD
Faculty Disclosure: No relationship with commercial
supporters.
Unlabelled/Unapproved
Uses:
No faculty member has indicated
that their presentation will include information
on off label products.
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Course
Directors
Edward E, Lawson, M.D.
Professor
Department of Pediatrics Neonatalogy
The Johns Hopkins University
School of Medicine
Lawrence M. Nogee, M.D.
Associate Professor
Department of Pediatrics Neonatalogy
The Johns Hopkins University
School of Medicine
Christoph U. Lehmann, M.D.
Assistant Professor
Department of Pediatrics,
Health Information
Science and Dermatology
The Johns Hopkins University
School of Medicine
Mary Terhaar, RN
Assistant Professor
Undergraduate Instruction,
The Johns Hopkins University
School of Nursing
Robert J. Kopotic, MSN,
RRT, FAARC
Director of Clinical Programs
ConMed Corporation
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Learning
Objectives
The
Johns Hopkins University School of Medicine and The Institute
for Johns Hopkins Nursing take responsibility for the content,
quality, and scientific integrity of this CE activity.
At
the conclusion of this activity, participants should be able to:
- Discuss why continuous monitoring in the NICU is essential
- Recognize that fifty to sixty percent of the neonatal seizures
are ‘subclinical’ (seizure discharges without clinical
manifestations)
- Summarize why neonatal seizures are difficult to treat
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Commentary |
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The incidence of neonatal seizures is 3.5/1000 live births1,
with hypoxic-ischemic brain injury the most common cause
of seizures in the neonatal period. Clinical manifestations
of neonatal convulsions are very diverse and not always
easy to recognize, especially when they are subtle. Continuous
EEG monitoring often reveals electrographic seizures (discharges
without clinical manifestations), especially following initiation
of therapy for clinical seizures2,3. Only with
the use of continuous monitoring can subclinical seizures
be detected. So far there is no agreement as to whether
these subclinical seizure discharges should be treated,
although some studies suggest an adverse effect on neurodevelopmental
outcome4,5. Recent findings in animal studies
show that neonatal seizures adversely affect the developing
brain, as do anti-epileptic drugs6-10.
Three recent publications2,3,11 show that anticonvulsants,
effective in adults, are not as effective in neonates. On
the other hand, the neonatal brain appears uniquely susceptible
to seizures because neonatal gamma-aminobutyric acid (GABA)
receptors are excitatory (instead of inhibitory as in adults),
and are functionally more active at this stage of life than
are N-methyl-D-aspartate receptors. In this context, the
hypothesis that a diuretic drug such as bumetanide could
be used as an anti-epileptic drug in neonates is of particular
interest12,13. The severity of the seizures appears to
be a stronger predictor of the success of treatment than
the assigned agent11, a hypothesis confirmed by Boylan
et al2, who report that electrographic seizures were
common in infants who had severe hypoxic ischemic encephalopathy,
particularly after treatment with phenobarbital.
Considering the potential harmful effect of anti-epileptic
drugs as described by Bittigau et al10, should
the clinician give a maintenance dose of anti-epileptic
drugs after the initial treatment of neonatal seizures to
prevent post-neonatal seizures? The question is further
complicated by the report by Toet et al14, showing
that post-neonatal epilepsy occurred in only 9.4 % of the
patients following treatment of clinical and subclinical
neonatal seizures. Following perinatal arterial stroke,
the incidence of post-neonatal epilepsy was higher (18%),
suggesting that that treatment of subclinical seizures may
be of additional value. With the “real EEG”
readings now available on the new digital aEEG machines,
seizures have become easier to differentiate from artifacts,
allowing for potential interventions.
The large variety of characteristics of the neonatal seizure
make automatic seizure detection methods very difficult
to implement, as was recently shown by Faul et al15.
The authors report that neonatal seizures tend to migrate
throughout the brain, contain rhythmic activity that can
vary in frequency, and that multifocal seizures are common
in neonates and often display simultaneous independent focal
electrographic signatures. The morphology of the electrographic
neonatal seizures also varies tremendously between individuals,
and can vary within the seizure. Further, neonatal seizures
often evolve in amplitude, but may suddenly end when reaching
a maximum, or may continue and gradually wane.
There remain many questions to be answered about how to
treat neonatal seizures most effectively. While continuous
(a)EEG monitoring is an essential tool in providing answers,
thoroughly effective and reliable automated neonatal seizure
detection remains a long way in the future.
References:
1. |
Volpe Neurology if the
Newborn, fourth edition 2001, chapter 5: W.B. Saunders
company. |
2. |
Boylan G.B, Pressler
R.M, Rennie J.M, Morton M, Leow P.L, Hughes R, Binnie
C.D. outcome
of electroclinical, electrographic, and clinical seizures
in the newborn infant. Dev Med& Child Neur 1999;
41: 819-825. |
3. |
Sher M.S, Alvin J, Gaus
L, Minnigh B, Painter M. J. Uncoupling
of EEG-clinical neonatal seizures after antiepileptic
drug use. Pediatr Neurol 2003; 28:277-280. |
4. |
Miller S.P, Weiss J,
Barnwell A, Ferriero D.M, Latal-hajnal B, Ferrer- Rogers
A, Newton N, Partridge J.C, Glidden D.V, Vigneron D.B,
Barkovich A.J. Seizure-associated
brain injury in term newborns with perinatal asphyxia.
Neurology 2002; 58: 542-548. |
5. |
McBride M.C, Laroia N,
Guillet R. Electrographic
seizures in neonates correlate with poor neurodevelopmental
outcome. Neurology 2000; 55; 506-513. |
6. |
Liu Z, Yang Y, Silveira
DC, Sarkinsian M.R, Tandon P, Huang L.T, Staftrom C.E,
Holmes G.L. Consequences
of recurrent seizures during early brain development.
Neuroscience 1999; 92: 1443-1454. |
7. |
Holmes G.L, Gairsa J.L,
Chevassus-au-Louis N, Ben-Ari Y. Consequences
of neonatal seizures in the rat: morphological behavioural
effects. Ann Neurol 1998; 44: 845-57. |
8. |
Holmes G.L. Seizure-induced
neuronal injury. Neurology 2002; 59: S3-S6. |
9. |
Wirrell E.C, Armstrong
E.A, Osman L.D, Yager J. Y. Prolonged
seizures exacerbate perinatal hypoxic-ischemic brain
damage. Pediatr Res 2001; 50: 445-454. |
10. |
Bittigau P, Sifringer
M, Genz K, Reith E, Pospischil D, Govindarajalu S, Dzietko
M, Pesditschek S, Mai I, Dikranian K, Olney J.W, Ikonomidou
C. Antiepileptic
drugs and Apoptosis in the developing brain. PNAS
2002; 99(23): 15089-15094. (Ann N.Y. Acad. Sci. 2003;
993: 103-104) |
11. |
Painter M.J, Sher M.S,
Stein A.D, Armatti S, Wang Z, Gardiner J.C, Paneth N,
Minnigh B, Alvin J. Phenobarbital
compared with Phenytoin for the treatment of neonatal
seizures. N Eng J Med 1999; 341: 485-489. |
12. |
Dzhala V.I, Talos D.M,
Sdrulla D.A, Brumback A.C, Mathews G.R, Benke T.A, Delpire
E, Jensen F.E, Staley K.J. NKCC1
transporter facilitates seizures in the developing brain.
Nature Medicin 2005; 11: 1205-1213. |
13. |
Fukuda A. Diuretics
soothes seizures in the newborns. Nature Medicin
2005; 11: 1153-1154. |
14. |
Toet MC, Groenendaal
F, Osredkar D, van Huffelen AC, de Vries LS. Post
neonatal seizures following aEEG detected neonatal seizures.
Pediatr Neurol 2005; 32: 241-247. |
15. |
Faul S, Boylan G, Connonly
S, Marnane L, Lightbody G. An
evaluation of automated neonatal seizure detection methods.
Clinical Neurophysiology 2005; 116: 1533-1541. |
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DIURETICS
SOOTHES SEIZURES |
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Dzhala
V.I, Talos D.M, Sdrulla D.A, Brumback A.C, Mathews
G.R, Benke T.A, Delpire E, Jensen F.E, Staley K.J.
NKCC1 transporter facilitates seizures in
the developing brain. Nature Medicine 2005;
11: 1205-1213. With a commentary of Dr Fukuda on this
paper:
(For non-journal subscribers,
an additional fee may apply for full text articles) |
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Fukuda A. Diuretics soothes seizures in the
newborns. Nature Medicine 2005; 11: 1153-1154.
(For non-journal subscribers,
an additional fee may apply for full text articles)
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Conventional anticonvulsant drugs often target the gamma-aminobutyric
acid (GABAA) chloride channel, which operates differently
in adult and infant brains. Immature neurons contain high
levels of chloride ions and express high levels of NKCC1,
a co-transporter that uses the electrochemical gradient of
both sodium and potassium to cause the accumulation of chloride
in neurons. Dzhala et al tested the hypothesis that inhibition
of NKCC1 activity with a drug that targets a chloride transporter
particularly active in children would reduce the concentration
of intracellular chloride in immature cortical neurons, which
in turn would reduce GABAA receptor-mediated excitation,
or convert the GABA response to inhibitory and thus provide
anticonvulsant effect.
The investigators found that NKCC1 was highly expressed
in both neonatal rat and human cortex and that bumetanide,
a diuretic drug, inhibited cortical seizure activity in
neonatal rats both in vitro and in vivo at doses that have
already been extensively tested/used in human neonates.
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PHENOBARBITAL
AND PHENYTOIN NOT VERY EFFECTIVE IN NEONATAL SEIZURES |
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Painter
M.J, Sher M.S, Stein A.D, Armatti S, Wang Z, gardiner
J.C, Paneth N, Minnigh B, Alvin J. Phenobarbital
compared with Phenytoin for the treatment of neonatal
seizures. N Eng J Med 1999; 341: 485-489.
(For non-journal subscribers,
an additional fee may apply for full text articles)
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Painter et al describe a single-blinded study for treatment
of neonatal seizures, wherein 59 infants (term and preterm)
were randomly assigned to treatment with phenobarbital or
phenytoin. Neonates whose seizures were not controlled by
the assigned drug were then treated with both drugs. All neonates
had continuous EEG recordings for 24 hours, starting from
the time of the EEG that determined their eligibility for
the trial, or until both drugs had proved to be ineffective.
Seizures control was assessed by EEG criteria.
The investigators found that seizures were controlled in
13 of the 30 neonates assigned to receive phenobarbital
(43%) and 13 of the 29 neonates assigned to receive phenytoin
(45%). When combined treatment was considered, seizure control
was achieved in 17 (57 %) of the neonates assigned to receive
phenobarbital first and in 18 (62%) of those assigned to
receive phenytoin first (p=0.67). The authors further note
that severity of the seizures was a stronger predictor of
the success of treatment than the assigned agent.
In summation, the authors found that phenobarbital and
phenytoin are both equally ineffective in complete seizure
control in neonates.
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THE
INCIDENCE OF POST-NEONATAL EPILEPSY AFTER NEONATAL SEIZURES
IS LOW |
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Toet
MC, Groenendaal F, Osredkar D, van Huffelen AC, de Vries
LS. Post neonatal seizures following aEEG detected
neonatal seizures. Pediatr Neurol 2005; 32:
241-247. (For
non-journal subscribers, an additional fee may apply
for full text articles) |
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Toet et al addressed the incidence of post-neonatal epilepsy
in full-term infants treated with anti-epileptic drugs for
neonatal seizure discharges, as detected with amplitude
integrated EEG (aEEG). 206 full-term infants were monitored
using aEEG, and received anti-epileptic drugs for clinical
as well as subclinical neonatal seizures. Follow-up data
were analyzed for the development of post neonatal epilepsy,
and their neurodevelopmental outcomes assessed at 3, 9,
18 months, 3 and 5 years of age. 169 (82%) neonates received
2 or more anti-epileptic drugs. Overall mortality was 39%
(n=80). 41 of the 126 survivors (33%) were abnormal at follow-up,
and 12 developed post-neonatal epilepsy (9.4 %).
84 children survived following hypoxic ischemic encephalopathy
Sarnat grade II (n=92) and 6 (7%) developed post-neonatal
epilepsy. In this subgroup no post-neonatal epilepsy was
seen if seizures were controlled within 48 hours after birth
and when not more than two anti-epileptic drugs were needed.
Twenty-four children survived following intracranial hemorrhage
(n=28) and only one (4%) developed post-neonatal epilepsy.
Eleven children survived following perinatal arterial stroke
(n=13) and 2 (18%) developed post-neonatal epilepsy.
In summation, the authors report that the incidence of
post-neonatal epilepsy following treatment of clinical and
subclinical neonatal seizures, detected with continuous
aEEG, was 9.4%, and was only found in infants with an abnormal
neurodevelopmental outcome. This figure is lower than previously
reported in children who only received treatment for clinical
seizures.
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ELECTROGRAPHIC
SEIZURES PERSIST AFTER ANTI-EPILEPTIC DRUG USE |
|
Sher
M.S, Alvin J, Gaus L, Minnigh B, Painter M. J. Uncoupling
of EEG-clinical neonatal seizures after antiepileptic
drug use. Pediatr Neurol 2003; 28:277-280.
(For non-journal subscribers,
an additional fee may apply for full text articles)
|
|
|
 |
Boylan G.B, Pressler R.M, Rennie J.M, Morton M, Leow
P.L, Hughes R, Binnie C.D. outcome of electroclinical,
electrographic, and clinical seizures in the newborn
infant. Dev Med& Child Neur 1999; 41:
819-825.
(For non-journal subscribers,
an additional fee may apply for full text articles)
|
|
|
 |
Sher et al describe a prospective study of the efficacy
of seizure cessation by phenobarbital versus phenytoin in
59 term and preterm neonates. They introduced the phenomenon
of uncoupling: the persistence of electrographic
seizures despite the suppression of >50% of the clinical
seizures following administration of either one or both
anti-epileptic drugs.
The authors found that 58% of the neonates with persistent
seizures after treatment had uncoupling of electrical and
clinical expression of seizures, with phenobarbital and
phenytoin resulting in equal rates of uncoupling. Twenty-four
infants responded to the first choice of an anti-epileptic
drug with no further seizures.
Boylan et al describe 3 seizure types in 24 neonates (electroclinical,
electrographic, and clinical only) using video-EEG for at
least 100 minutes within 12 hours of the first seizure.
Griffiths neurodevelopmental outcome was assessed in all
groups. One of their findings was that electrographic seizures
were common in infants who had severe hypoxic ischemic encephalopathy,
particularly after phenobarbital treatment.
Both authors found that electrographic neonatal seizures
without clinical seizures are very common following anti-epileptic
drugs.
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AUTOMATED
NEONATAL SEIZURE DETECTION: STILL A LONG WAY TO GO |
 |
Faul
S, Boylan G, Connonly S, Marnane L, Lightbody G. An
evaluation of automated neonatal seizure detection methods.
Clinical Neurophysiology 2005; 116: 1533-1541.
(For non-journal subscribers,
an additional fee may apply for full text articles)
|
|
|
 |
Faul et al evaluated 3 published automated algorithms (Gotman,
Liu and Celka) for detecting seizures in neonatal EEG. They
tested 43 data files (one-minute, artifact-free EEG segments)
containing seizure activity and 34 data files free from
seizure activity. In an attempt to obtain improved detection
rates, threshold values in each algorithm were manipulated
and the actual algorithms were altered. The sensitivity
of the 3 algorithms was respectively 62.5, 42.9 and 66.1%
with a specificity of 64.0, 90.2 and 56.0%.
The authors conclude that the levels of performance achieved
by automated seizure detection algorithms are not high enough
for clinical use, reflecting the difficulties involved in
detecting seizures in neonates and the lack of a reliable
detection scheme for clinical use. The overlap of the frequency
characteristics of seizure and non-seizure EEG, artifacts,
and natural variances in the neonatal EEG cause great difficulties
with the seizure detection algorithms. The algorithm performances
figures for this neonatal data set are considerably worse
than quoted in the original algorithm source papers.
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ADVERSE
EFFECTS OF ANTI-EPILEPTIC DRUGS ON THE DEVELOPING BRAIN |
 |
Bittigau
P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu
S, Dzietko M, Pesditschek S, Mai I, Dikranian K, Olney
J.W, Ikonomidou C. Antiepileptic drugs and Apoptosis
in the developing brain. PNAS 2002; 99(23):
15089-15094. (Ann N.Y. Acad. Sci. 2003; 993: 103-104)
(For non-journal subscribers,
an additional fee may apply for full text articles)
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Wistar rats 0-30 days old received i.p. administration
of anti-epileptic drugs, β-estradiol, or normal saline,
and were allowed to survive for up to 48 hours after injection.
Their brains were analyzed 24 hours later. The investigators
looked at histology of the whole brain to visualize degenerating
cells and quantify the damage. In addition, total cellular
RNA was isolated and total cellular proteins were separated.
In this animal model, the investigators show that at plasma
concentrations relevant for seizure control in humans, phenytoin,
phenobarbital, diazepam, clonazepam, vigabatrin, and valproate
all cause apoptotic neurodegeneration. The combination of
anti-epileptic drugs with different modes of action appears
to result in a substantially higher apoptotic response compared
to monotherapy.
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LAST
MONTH�S Q & A April 2006 - Volume 3 -
Issue 8
Last
issue we reviewed the increasing use of continuous (a)EEG
monitoring in the NICU, with a particular focus on subclinical
seizures, and discussed the effectiveness and risk/reward
of anti-epileptic drugs in neonates.
|
Commentary
& Reviews:
Mona C. Toet
Neonatologist
Wilhelmina Children's Hospital, UMCU,
The Netherlands |
|
|
Commentary
& Reviews:
Linda de Vries
Professor in Neonatal Neurology
Wilhelmina Children's Hospital, UMCU,
The Netherlands |
|
We
received the following questions from one of our subscribers. |
|
As
described in the issue, phenobarbitone and phenytoin
have been shown to be ineffective in controlling seizures.
Which other anti-epileptics are recommended? |
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Benzodiazepine drugs such as midazolam and lorazepam
are commonly used to control neonatal seizures. However,
as there is a sedative effect with these agents that
may mask subclinical seizure activity, the clinician
should be aware that subclinical seizures may continue
in spite of absence of clinical seizures.
Reference:
1. Boylan G.B, Rennie J.M, Chorley G et al. Second-line
anticonvulsant treatment of neonatal seizures.
Neurology 2004; 62 (3):486-8. |
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Is
there a role for lignocaine (lidocaine) in controlling
neonatal seizures? |
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We
and others have also used lignocaine, which, in our
experience, appears to be more effective than the
benzodiapines in controlling seizures. However, the
drug should only be used in an intensive care setting,
as it presents a risk (although a low one) for cardiac
arrythmias. In addition, as both phenytoin and lignocaine
have a proarrythmic effect, it is not recommended
to use lignocaine following administration of phenytoin.
References:
1. Hellström-Westas L, Svenningsen NW, Westgren
U, Rosen I, Lagerstrom PO. Lidocaine
for treatment of severe seizures in newborn infants.
II. Blood concentrations of lidocaine and metabolites
during intravenous infusion. Acta Paediatr 1992;
81(10):35-9.
2. Malingre M et al. Development of an optimal lidocaine
infusion strategy in neonatal seizures: In press:
Eur J Pediatr |
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There are no fees or prerequisites for this activity.
Learning Objectives
� back
to top
At the conclusion of this activity, participants should
be able to:
- Discuss why continuous monitoring in the NICU is essential
- Recognize that fifty to sixty percent of the neonatal seizures
are ‘subclinical’ (seizure discharges without clinical
manifestations)
- Summarize why neonatal seizures are difficult to treat
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