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Nej MR A 2300188
Nej MR A 2300188
Review Article
Neonatal Seizures
Elissa Yozawitz, M.D.
N
From the Isabelle Rapin Division of Child eonatal seizures are defined as seizures occurring within
Neurology of the Saul R. Korey Depart- 4 weeks after birth in full-term infants or within 44 weeks of postmen-
ment of Neurology, Montefiore Medical
Center, Albert Einstein College of Medi- strual age in preterm infants. The estimated incidence of these seizures
cine, Bronx, NY. Dr. Yozawitz can be con- is 2.29 cases per 1000 live births. Higher rates have been reported among preterm
tacted at eyozawit@montefiore.org or at neonates than among full-term neonates (14.28 cases per 1000 vs. 1.10 per 1000).1
3415 Bainbridge Ave, 4th Fl., Bronx, NY
10467. The International League against Epilepsy (ILAE) has developed a diagnostic
framework to classify neonatal seizures,2 which facilitates the use of common
N Engl J Med 2023;388:1692-700.
DOI: 10.1056/NEJMra2300188 terminology and assists clinicians in making treatment decisions. Most neonatal
Copyright © 2023 Massachusetts Medical Society. seizures are transient and result from acute metabolic disturbances, infectious
processes, or acute focal cerebral lesions. Such seizures are considered to be pro-
CME
at NEJM.org voked. In full-term neonates, the most common cause of provoked seizures is
hypoxic ischemic encephalopathy, followed in frequency by stroke and infection.
In preterm neonates, the most common cause is intraventricular hemorrhage.
Identifying the provoking event is essential for determining management.
Provoked seizures are not considered to be epilepsy, which is defined as two or
more unprovoked seizures, and provoked seizures typically do not require long-
term treatment with antiseizure medication.3 Neonatal epilepsy syndromes, which
are uncommon, frequently have genetic causes, and unlike provoked seizures,
some of these syndromes require long-term treatment.4
A systematic review has suggested that clini- Table 1. Levels of Diagnostic Certainty.*
cal seizure types are usually associated with
specific underlying causes.7 For example, focal Course of
Level Definition Action
clonic seizures usually signify a cerebral infarc-
tion and the need for cranial imaging to con- Level 1: Suspected seizure with a continuous Treat
Definite seizure EEG correlate
firm the diagnosis. Tonic seizures are seen
mainly with hypoxic ischemic encephalopathy Level 2: Suspected seizure with an amplitude- Treat
Probable seizure integrated EEG correlate or clini-
but also with metabolic disorders, channelopa- cally assessed focal clonic or tonic
thies, vascular disorders, or cortical malforma- seizure
tions. When the presentation includes myoclonic Level 3: Clinical seizure other than focal tonic Consider treat-
seizures (sudden, brief, irregular limb contrac- Possible seizure or clonic ment
tions), metabolic disorders such as hypoglyce- Level 4: Insufficient evidence to meet seizure Do not treat
mia or hyponatremia, amino acid disorders, or Suspected seizure criteria
other inborn errors of metabolism are usually Level 5: Movement determined by EEG not to Do not treat
responsible. Sequential seizures are defined by Not a seizure be a seizure
the occurrence of more than one seizure type * Seizures defined as definite or probable should be managed with antiseizure
during an episode and are often genetically medication. If electroencephalography (EEG) is not available, the clinician can
determined. Epileptic spasms (sudden flexion, rely on levels 3, 4, and 5, deciding whether an event is a seizure solely on the
basis of clinical semiology. The levels of diagnostic certainty were proposed
extension, or mixed flexion with extension of by the Brighton Collaboration.
the proximal and truncal muscles) also suggest
genetic causes. Autonomic seizures are charac-
terized by alterations in cardiovascular, vasomo-
E va luat ion of Neonata l
tor, or respiratory patterns and are typically ob- Sei zur e s
served in neonates with hypoxic ischemic
encephalopathy or intracranial hemorrhage. The initial steps in managing neonatal seizures
Some of these etiologic associations are based are to stabilize cardiovascular and respiratory
on current opinion, and prospective studies with function and then to identify the cause of the
large cohorts of neonates are needed to con- seizures. Treatable medical abnormalities, such
firm them. as hypoglycemia and electrolyte disorders (e.g.,
Several common nonepileptic motor phenom- hyponatremia), can be rapidly detected and cor-
ena may be difficult to differentiate from sei- rected, usually leading to cessation of seizures
zures in neonates. Tremor, jitteriness, and some without the need for antiseizure medication.
myoclonic movements can be mistaken for sei- EEG monitoring should be initiated as early as
zures. They can occur without obvious cause or possible to establish the presence of seizures
as symptoms of drug withdrawal, electrolyte because some types of seizures tend to peak in
abnormalities, hypoglycemia, or infection. They incidence and severity within the first 24 hours,
do not have EEG correlates and are not seizures. particularly those due to hypoxic ischemic en-
If EEG is not available, the aforementioned levels cephalopathy (Fig. 1).
of diagnostic certainty can be used to assess the Perinatal, birth, and family histories can pro-
likelihood that a paroxysmal movement is a sei- vide clues to the underlying cause of seizures.
zure. A common self-limiting neonatal condi- For example, some seizures, such as those due
tion, benign neonatal sleep myoclonus, is char- to nonketotic hyperglycinemia, begin prenatally,
acterized by myoclonic events that occur during and women may describe episodes of frequent,
sleep, with a normal EEG. Neonatal hyperek- continuous, rhythmic jerking of the fetus. Cer-
plexia is a rare disorder of muscle rigidity, tain examination findings also suggest specific
exaggerated startle reaction, and nocturnal causes of seizures: microcephaly may indicate
myoclonus, with a normal EEG, and is also not cerebral dysgenesis, genetic abnormalities, or
an epilepsy syndrome. The attacks can be stopped congenital infection; macrocephaly may be due
by the Vigevano maneuver, consisting of to structural or genetic abnormalities; dysmor-
forced f lexion of the head and legs toward the phic features suggest cerebral dysgenesis, often
trunk. due to a genetic abnormality; neurocutaneous
Suspected Metabolic
Urgent Evaluation Suspected HIE Suspected Infection Suspected Stroke Disorder
Obtain immediate labor Check birth history and Obtain blood cultures Imaging: MRI with diffusion- Screen for other metabolic
atory measurements, Apgar score; screen and TORCH titers; weighted imaging; abnormalities (screen in-
including glucose, for other causes, CSF studies: glucose evaluate for cause (e.g., cludes amino acids, am-
electrolytes, and full depending on clini- and protein, cell counts, thrombophilia or vas- monia, lactate, pyruvate,
blood count; confirm cal scenario; assess PCR assay for HSV, cular or cardiac cause); very-long-chain fatty acids,
with EEG or amplitude- need for therapeutic culture; pathological echocardiogram; patho- urine, organic acids, bio-
integrated EEG hypothermia assessment of pla- logical assessment of tinidase, pipecolic acid,
centa placenta pyridoxine, pyridoxal-
5-phosphate); ophthal-
mologic evaluation
* CSF denotes cerebrospinal fluid, HIE hypoxemic ischemic encephalopathy, HSV herpes simplex virus, PCR polymerase chain reaction, MRI
magnetic resonance imaging, and TORCH toxoplasmosis, other (syphilis, varicella, mumps, parvovirus, human immunodeficiency virus,
and Zika), rubella, cytomegalovirus, and HSV.
Table 3. Approximate Doses of the Main Antiseizure Medications for the Treatment of Neonatal Seizures.*
* Information on doses is from Dehkharghani,12 Sharpe et al.,13 Van Den Broek et al.,15 Pisano et al.,16 Castro Conde et al.,17 Sands et al.,18
Favié et al.,19 and Pressler et al.3 Other agents that may be used, depending on the clinical presentation, family history, laboratory tests,
and EEG findings, include pyridoxine, pyridoxal-5-phosphate, and carbamazepine. FDA denotes Food and Drug Administration, GABAA
γ-aminobutyric acid type A, and SV2A synaptic vesicle protein 2A.
† Opinions about dosing vary, and the doses shown should be taken as approximate values.
‡ Higher doses of phenobarbital may be given with careful cardiorespiratory monitoring.
prognostic and treatment recommendations. zures are due to loss-of-function KCNQ2 and
They can be divided into two broad categories: KCNQ3 variants.3,18
self-limited epilepsies, which in turn have two Early infantile developmental and epileptic
subcategories, and developmental and epileptic encephalopathy is a newly characterized entity
encephalopathies (Fig. S1 in the Supplementary that is manifested as medication-resistant sei-
Appendix, available with the full text of this ar- zures of various types in the first 3 months of
ticle at NEJM.org).22 Developmental and epileptic life, associated with severe developmental im-
encephalopathies are defined by intractable sei- pairment, abnormal findings on neurologic ex-
zures associated with developmental impair- amination, and an EEG background with burst
ment or regression often due to an underlying suppression (Fig. S2) or multifocal epileptiform
cause (which is likely to be genetic, structural, discharges with diffuse slowing.4 Neuroimag-
or metabolic).23 ing, genetic testing, and metabolic studies show
The self-limited neonatal epilepsy syndromes an underlying cause in up to 80% of infants.25,26
are due to pathogenic variants, either familial These cases are rare and do not have a distinct
or de novo, most commonly in KCNQ2 and, less clinical phenotype, as described below. The
commonly, in KCNQ3,4 as described below, or numbers and individual cause–specific syn-
SCN2A.24 The typical self-limited epilepsy syn- dromes in this group are likely to increase as
drome begins between 2 and 7 days after birth more pathogenic variants are found. Currently,
and remits after 6 months. Clues to this diag- none of the conventional antiseizure medica-
nosis are a family history of seizures and focal tions, including glucocorticoids and pyridoxine,
and tonic seizures at the onset of an episode, stop the seizures. Nevertheless, treatment can
but the syndrome may sometimes include focal be targeted at an underlying metabolic disorder,
clonic, tonic, or sequential manifestations.2 if present (e.g., aminoacidopathies or organic
Sodium-channel blockers are used when sei- acidemias). Surgical removal of a focal lesion
(including cortical dysplasias, hemimegaloen- jury, often with a genetic cause, and have a poor
cephaly, and cortical tubers), if present, may be overall prognosis.
considered after the failure of two or more drug Untreated seizures can cause hippocampal
trials.27,28 These neonates may have coexisting sclerosis and worsen the clinical outcome, re-
movement disorders, cortical visual impair- gardless of the cause.31,32 Despite this generally
ments, feeding difficulties, or orthopedic prob- accepted tenet, the extent to which seizures can
lems due to abnormal muscle tone and contrac- potentiate brain injury is unclear.33 Analyses of
tures. data from several case series have shown that
Three additional developmental and epileptic status epilepticus or seizures lasting longer than
encephalopathies have been described, with spe- 12 to 13 minutes per hour are associated with a
cific pathogenic variants and relatively uniform poor outcome, which is independent of the
and distinct clinical phenotypes. KCNQ2-associ- cause.34-37 However, there is no definitive evi-
ated developmental and epileptic encephalopa- dence that isolated seizures of brief duration
thy begins in the first few days of life, and the have a negative outcome. Studies in animals
semiology is characterized by focal tonic seizures. suggest that the immature brain may be less
However, focal clonic and myoclonic seizures susceptible to injury from seizures than the
can also occur.29 Encephalopathy is present more mature brain. In two common animal
when the seizures begin. models of status epilepticus, hippocampal injury
Pyridoxine-dependent developmental and epi- was not easily induced in rats that were less than
leptic encephalopathy and pyridoxal phosphate 21 days old.33
deficiency–associated developmental and epilep- Certain patterns on EEG can assist in deter-
tic encephalopathy, mentioned above, are nota- mining the prognosis for neonates with clini-
ble genetic syndromes because their treatment cally confirmed EEG seizures and for those
differs from that of other neonatal epilepsies. with only EEG evidence of seizure activity.38,39
Patients with these disorders present within the Background burst suppression and ictal activ-
first hours to days of life with encephalopathy ity are associated with a poor prognosis,
and intractable seizures. Seizures are frequent, whereas normal background activity suggests
often evolving into status epilepticus with focal a better prognosis.40 In a study involving neo-
or multifocal myoclonic movements of the face, nates with hypoxic ischemic encephalopathy,
arms, legs, and trunk; epileptic spasms may also normal or mildly abnormal background EEG
occur. Another disorder, CDKL5-associated de- activity was found to be predictive of a normal
velopmental and epileptic encephalopathy, typi- developmental outcome.41 Controlling sei-
cally develops within the first few weeks of life, zures before the end of the second day after
and the seizures are drug-resistant. Neonates delivery is also associated with a favorable
with this disorder typically present with hypoto- outcome.42,43
nia and sequential seizures with hyperkinetic,
tonic epileptic spasms. Sum m a r y
The ILAE has proposed new guidelines for de-
Pro gnosis a nd C ompl ic at ions
fining and classifying neonatal seizures. These
The prognosis for neonatal seizures varies ac- new syndrome definitions and classifications,
cording to the cause, age at onset, seizure dura- along with access to genetic testing, have re-
tion, and responsiveness to medication. Rapid shaped how clinicians view and manage neona-
recognition and treatment are considered the tal seizures. Neonatal age, the age at the onset
best ways to prevent adverse effects of the sei- of seizures, and clinical semiology provide clues
zures and to improve long-term outcomes.30 Al- to the cause of seizures, which in turn lead to
though self-limited epilepsy syndromes, de- tailored treatments, and current practice stress-
scribed above, are characterized by frequent es the importance of EEG monitoring.
seizures, they remit spontaneously, with a typi- Disclosure forms provided by the authors are available with
cally good prognosis. At the other extreme are the full text of this article at NEJM.org.
the developmental and epileptic encephalopa- I thank Dr. Solomon Moshé for suggestions on an earlier ver-
thies, which are due to severe, diffuse brain in- sion of the manuscript.
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