Clinical features, evaluation, and diagnosis of neonatal seizures

INTRODUCTION — The occurrence of neonatal seizures may be the first, and perhaps the only, clinical sign of a central nervous system (CNS) disorder in the newborn infant. As such, seizures may indicate the presence of a potentially treatable etiology and should prompt an immediate evaluation to determine cause and to institute etiology-specific therapy. In addition, seizures themselves require emergent therapy, since they may adversely affect the infant's homeostasis or contribute to further brain injury.

The clinical features, evaluation, and diagnosis of neonatal seizures will be reviewed here. The etiology and treatment of neonatal seizures and associated epilepsy syndromes are discussed separately. (See "Etiology and prognosis of neonatal seizures" and "Overview of neonatal epilepsy syndromes" and "Treatment of neonatal seizures".)

EPIDEMIOLOGY — Seizures occur more often in the neonatal period than at any other time of life; during this period, they most often occur within the first week of life [1,2]. Reported incidence ranges from 1.5 to 5.5 per 1000 in newborns [2-4] and may be even higher in premature infants [5,6]. Seizure incidence varies with some specific risk factors. Occurrence increases with decreasing gestational age and birth weight, and with increasing acuity of illness [2,7-9].

ETIOLOGY — The causes of neonatal seizures are summarized in the tables (table 1 and table 2). Most neonatal seizures (approximately 85 percent) are acute provoked seizures (previously called acute symptomatic seizures), occurring as a consequence of a specific identifiable etiology [10-14]. These acute provoked seizure etiologies can be broadly categorized as:

●Neonatal encephalopathy and hypoxic-ischemic encephalopathy

●Structural brain injuries, including ischemic and hemorrhagic stroke

●Metabolic disturbances (most often glucose and electrolyte abnormalities)

●Central nervous system (CNS) or systemic infections

Epilepsy syndromes account for approximately 15 percent of all neonatal seizures [15]. Neonates with seizures in the context of cerebral dysgenesis have epilepsy. Neonates with normal brain imaging can also have epilepsy. In well-appearing neonates with a negative work-up, recurrent neonatal seizures may be due to a genetic epilepsy syndrome such as self-limited neonatal epilepsy (previously called benign familial neonatal epilepsy). By contrast, severe neonatal epilepsy syndromes such as early infantile developmental and epileptic encephalopathy (previously called early myoclonic encephalopathy and early infantile epileptic encephalopathy or Ohtahara syndrome) are associated with an abnormal neurologic examination and a poor prognosis.

The etiology and prognosis of neonatal seizures and neonatal epilepsy syndromes are discussed in more detail separately. (See "Etiology and prognosis of neonatal seizures" and "Overview of neonatal epilepsy syndromes".)

CLINICAL FEATURES — Seizures in the neonate have unique clinical features when compared with those of older infants and children. There are age-dependent properties of the immature brain that enhance seizure initiation, maintenance of the seizure discharge, and propagation of the seizure discharge [16]. The clinical events that are most consistently due to neonatal seizures are focal clonic, focal tonic, some types of myoclonic, and epileptic spasms. Nonseizure paroxysmal events are common in this age group and can sometimes be difficult to distinguish from seizures. (See 'Differential diagnosis' below.)

While neonatal seizures are now defined by their electroencephalographic signature [14], most earlier classifications categorized seizures according to their motor manifestations (focal clonic, multifocal clonic, generalized tonic, myoclonic, and subtle) [17-24]. The "subtle" semiology refers to seizures with signs such as abnormal eye movements, lip smacking, swimming or pedaling movements, or apnea (table 3 and table 4). Neonatal seizures remain distinct entities according to the International League Against Epilepsy (ILAE) seizure classification [14,25].

Electrographic-only seizures — Most neonatal seizures are electrographic-only, characterized by the presence of an electrographic seizure on electroencephalography (EEG) that has no overt clinical manifestations [13,26-30]. Electrographic-only seizures were previously termed "subclinical" or "silent" seizures [14]. A preverbal infant cannot communicate sensory phenomena associated with seizures (eg, a visual change associated with an occipital seizure or a sense of déjà vu due to a temporal lobe seizure), and unless the seizure originates in or migrates to the motor cortex, there will generally not be a clear abnormal movement. In a single-center review of 400 continuous video EEG studies performed in critically ill neonates, electrographic seizures were captured in 26 percent of monitored patients, and 24 percent of seizures had no clinical correlate (ie, electrographic-only) [31]. Others have reported much higher rates of electrographic-only seizures [26-29].

Clinical seizure types — A typical electroclinical neonatal seizure is a sequence of clinical events that may include different movements or behaviors that may occur at different times within the same seizure. Importantly, neonatal seizures are not generalized but focal (either unifocal or multifocal) [14,32]. Clinical semiologies are further subcategorized as focal, multifocal, bilateral asymmetric, and bilateral symmetric.

Note that an infant with electroclinical seizures may have resolution of the clinical seizure semiology with treatment but persistent electrographic-only seizures (electro-clinical uncoupling) [28]. (See 'Electrographic-only seizures' above.)

Focal clonic — Focal clonic seizures consist of repetitive, rhythmic contractions of specific muscle groups of the limbs, face, or trunk. Clonic movements typically have a slow rate of repetition, particularly when larger muscle groups are involved. They have a close relationship to the EEG seizure pattern, with each contraction having a consistent, time-locked relationship to EEG seizure discharges.

Compared with nonseizure movements such as clonus or tremor, the jerking movements of a focal clonic seizure are consistently slower and more rhythmic. Focal clonic seizures can be differentiated from tremor or clonus by restraint of movement. Tremor or clonus can be stopped by restraint, though clonic seizure activity cannot, and muscle twitching can still be felt in the restrained limb.

While focal clonic seizures may be the most easily recognized by observers, these events do have features that may be unique to the neonatal period. Focal clonic seizures may be unifocal, confined to specific muscle groups including those of the proximal or distal limbs, trunk or neck, or regions of the face. Focal seizures may alternate between sites of involvement within the same seizure. Focal seizures may be multifocal and may exhibit clonic activity simultaneously but asynchronously. If all four limbs are involved, this may give the appearance of a generalized seizure; however, more careful inspection reveals that the limbs are not moving synchronously.

Focal seizures can migrate from one region to another. Migration may be according to traditional Jacksonian features (ie, contiguous spread over the cortical representation of the limbs, face, and trunk) or may be more erratic in spread. Focal seizures may also be hemiconvulsive. In this case, a seizure may be initially confined to the hand on one side of the body and then abruptly involve the remainder of that side of body without an intervening Jacksonian march.

Focal tonic — Focal tonic seizures occur less often than focal clonic seizures. Focal tonic seizures are characterized by sustained, but transient, asymmetrical posturing of the trunk or extremities or tonic deviation of the eyes. Seizures involving the limbs or trunk may appear as unilateral flexion of the trunk with the body pulling down and to one side or sustained flexion or extension of a limb. When the eyes are involved, there is sustained conjugate deviation of the eyes to one side. Any of these events are typically associated with focal EEG seizure activity.

Tonic seizures are the hallmark of several neonatal epilepsy syndromes (eg, KCNQ2 developmental and epileptic encephalopathy) [33]. Therefore, prominent focal tonic semiology should trigger consideration of neonatal-onset epilepsy as the etiology. (See "Overview of neonatal epilepsy syndromes", section on 'Developmental and epileptic encephalopathies'.)

Myoclonic — Myoclonic movements in neonates represent a diverse range of causes, some of which are seizures and others which are not. The movements of myoclonic seizures are characterized by contractions of muscle groups of well-defined regions: proximal or distal limb regions, entire limbs, trunk or diaphragm, or face. The movements are of variable speed depending upon the size of the muscle group involved. The movements may be isolated events or may be repetitive; when repetitive the rate of recurrence may be slow, irregular, or erratic.

Myoclonic seizures are distinguished from clonic seizures by the regular rate of repetition and persistence of clonic events. Myoclonic seizures can be classified as focal, generalized, or fragmentary. Focal myoclonic seizures have features similar to focal clonic seizures except that myoclonic events are nonrepetitive and erratic. Generalized myoclonic seizures include bilateral, symmetric jerking of all extremities and/or muscles of the trunk and neck. Fragmentary myoclonus is characterized by rapid, simultaneous but asynchronous, twitching of various small muscle groups that are typically distal. Fragmentary myoclonus is typically nonepileptic in origin.

Some myoclonic seizures occur with a consistent EEG signature, but others may not. This reflects the fact that some myoclonic seizures are generated at a cortical level and others are generated at more caudal levels such as subcortical structures, brainstem, spinal cord, or neuromuscular junction. In addition, some myoclonic seizures may be provoked by stimulation and suppressed by limb restraint or body repositioning.

Epileptic spasms — Epileptic spasms may occur in neonates, although they are rare. Epileptic spasms primarily involve truncal muscles and limbs. They are flexor, extensor, or mixed flexor-extensor. The clinical appearance of the events may be affected by the body position of the neonate at the time of the seizure. The epileptic spasm begins with an initial muscle contraction that is transiently maintained, followed by relaxation of the muscle.

These seizures typically occur in clusters and are most often present upon arousal of the infant from sleep. On EEG, the seizures may be associated with a diffuse, high-voltage, slow-wave transient, or with generalized voltage attenuation. (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis".)

Sequential seizures — As the name implies, sequential seizures have a sequence of clinical signs within individual seizures (as opposed to an infant having multiple distinct seizure semiologies) [14]. As an example, there may be a sequence of tonic then clonic movements, followed by automatisms and autonomic signs, within a single seizure; there is no predominant feature. The semiologies occur in a sequential pattern that may change in lateralization within or between seizures. This seizure type should raise suspicion for a genetic neonatal epilepsy.

Autonomic signs — Clinical changes related to the autonomic nervous system have been reported to be manifestations of neonatal seizures. These changes include: alterations in heart rate, respiration and blood pressure, flushing, salivation, and pupil dilatation [22,34,35]. However, the occurrence of any of these findings in isolation as true electroclinical seizures is rare. When they do occur, they do so most consistently in association with other clinical motor manifestations of seizures [19,36]. (See 'Abrupt changes in vital signs' below.)

DIFFERENTIAL DIAGNOSIS — Seizures in the neonate can be difficult to distinguish from abnormal, nonseizure paroxysmal events or normal newborn behaviors, and EEG is often required to distinguish among them (algorithm 1). As demonstrated by the following studies, bedside clinical observation is inadequate for accurate neonatal seizure diagnosis [19,37,38]:

●In one study, neonatal intensive care unit (NICU) nurses and physicians were trained to record every suspected seizure event for a sample of high-risk neonates who were undergoing conventional EEG recording. Just 9 percent (48 of 526) of all EEG-confirmed seizures had clinical manifestations that were noted in the bedside logs, while 78 percent (129 of 177) of the abnormal paroxysmal events documented by NICU clinicians had no EEG correlate (ie, the documented events were not seizures) [37].

●In another study, 137 nurses and doctors reviewed video recordings of electroclinical seizures (EEG-confirmed seizures that had definite clinical manifestations) and nonseizure events (clinically-apparent events that had no corresponding EEG change) [38]. Interobserver agreement was poor (multi-rater kappa 0.21-0.29), and although two-thirds of clonic seizures were correctly diagnosed, only one third of seizures with other semiologies were accurately identified. Importantly, less than half of nonseizure events (eg, nonseizure clonus, benign sleep myoclonus, and other non-specific movements) were classified correctly.

Inaccurate neonatal seizure diagnosis has important consequences. Neonates with electrographic-only seizures are undertreated without EEG screening, while those whose paroxysmal events are not seizures may be exposed to unnecessary medications. (See 'Diagnosis' below.)

Nonseizure events — Neonatal seizures are generated by hypersynchronous cortical neuronal discharges. They are defined by their EEG patterns and may be electroclinical or electrographic-only. When infants are examined while they are experiencing electroclinical seizures, such as focal clonic or focal tonic seizures, the clinical event cannot be suppressed by restraint or repositioning of the affected limb. In addition, between seizures, clinical events cannot be provoked by stimulation of the infant.

By contrast, nonseizure events occur in the absence of any abnormal paroxysmal ictal rhythm on EEG [1,19]. They can sometimes be provoked by stimulation of the infant, and both the provoked and spontaneous events can typically be suppressed by restraint of the infant or by repositioning the infant during the event. In addition, the clinical events may increase in intensity with the increase in the repetition rate of stimulation (temporal summation) or the sites of simultaneous stimulation (spatial summation).

Examples of nonseizure neonatal events include various motor automatisms (table 4) and tonic posturing. Like seizures, nonseizure paroxysmal events in the neonate are often symptomatic of underlying nervous system pathology and should be evaluated systematically.

●Motor automatisms – Motor automatisms may appear as oral-buccal-lingual movements, including episodic chewing, swallowing, sucking, or repetitive tongue movements. Ocular movements appear as episodic random or oscillatory eye movements, repetitive eye opening, episodic and nonsustained eye deviation, or episodic dysconjugate gaze. Progression movements resemble pedaling or bicycling movements of the legs, swimming-like movements, rotary movement of the upper extremities, or combinations of these movements. In the past, the term "motor automatisms" was used to characterize these clinical events and these were referred to by some as "subtle seizures." Although these events are sometimes associated with electroclinical seizures, most often they are not (table 4). Motor automatisms can often be provoked by stimulation and are considered a manifestation of brainstem release phenomena. However, unless they have associated EEG correlates, they are not seizures.

●Tonic posturing – Bilateral, symmetric tonic posturing may be predominantly flexor, extensor, or mixed. The tonic posture is sustained and may involve bilateral limbs and the trunk. The muscle contractions are relatively long and are of greater duration than spasms. These tonic events can be provoked by stimulation and suppressed by restraint or repositioning of the infant. These events may occur in isolation, or they may occur in infants who are also experiencing motor automatisms.

Both motor automatisms and tonic posturing are considered to be of nonepileptic origin (ie, not seizures) if they have no associated ictal rhythm on EEG. They have clinical features that resemble exaggerated reflex behavior. They occur in infants who are obtunded or lethargic and with EEG background characterized as depressed and undifferentiated, features indicating the presence of forebrain depression. Tactile stimulation of the infants may provoke posturing or motor automatisms. These characteristics are based in reflex physiology and the events have been referred to as "brainstem release phenomena" [1,19].

Other paroxysmal events in the neonate that can be confused with seizures include hyperekplexia, jitteriness, tremulousness, and clonus. Such events can occur in normal and abnormal infants and can be differentiated from other clinical events, particularly focal clonic seizures, by their suppression by restraint. The clinical phenomenology of these nonepileptic paroxysmal events, especially in relation to how they are distinguished from epileptic seizures, is discussed separately. Importantly, clinicians have been shown to be inaccurate in distinguishing nonseizure paroxysmal events from electroclinical seizures [37,38]. (See "Nonepileptic paroxysmal disorders in infancy".)

Normal newborn behaviors — Neonatal seizures must be differentiated from normal, nonseizure behaviors of the newborn. Some normal behaviors of preterm and full-term infants may raise suspicions of seizures. Normal behaviors include stretching, nonspecific random movements that can be sudden (particularly in preterm infants), random sucking movements, coughing, and gagging.

In addition, neonates may experience normal physiologic myoclonus during active sleep (the precursor of rapid eye movement [REM] sleep). Myoclonus may also occur during quiet or non-REM sleep and has been referred to as benign neonatal myoclonus [39]. Importantly, if the neonate is otherwise healthy, the myoclonus virtually always ceases when the infant is awoken, and it only occurs when the neonate is asleep. This may help to distinguish this common phenomenon from neonatal seizures. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Benign neonatal sleep myoclonus'.)

Abrupt changes in vital signs — Most abrupt changes in blood pressure, heart rate, and respirations recorded in infants in the neonatal intensive care unit (NICU) are not manifestations of seizures [27,36]. When changes in these parameters are manifestations of seizures, they most often occur in association with motor phenomena or other clinical manifestations of seizures.

This was illustrated by a retrospective study of 324 continuous video EEG studies performed for the evaluation of paroxysmal vital sign changes in children [36]. Most of the studies were performed in neonates and infants less than one year old, and an index event was captured in 52 percent of the studies. The recorded vital sign changes were rarely related to seizures when the change was hypotension (0 out of 12), hypertension (1 out of 22, 4.5 percent), or bradycardia (2 out of 26, 7.7 percent), and all seizures were associated with additional clinical signs. Vital sign changes were more likely to be ictal when the change included oxygen desaturation (11 out of 82, 13 percent) or apnea (22 out of 83, 27 percent), particularly when accompanied by abnormal eye movements or an abrupt decrease in tone. Tachycardia with or without additional clinical signs was a seizure manifestation in 2 out of 23 studies (9 percent).

DIAGNOSIS — Historically, the diagnosis of neonatal seizures was most often made based on clinical signs. However, modern EEG studies have demonstrated that not all clinically suspicious events are epileptic seizures (in fact, most are not), and most neonatal seizures are electrographic-only [40].

Contemporary diagnosis of neonatal seizures therefore relies on confirmatory EEG characteristics (algorithm 1). When at-risk infants undergo EEG monitoring, high rates of both false positive and false negative clinical diagnoses are demonstrated (27 and 81 percent, respectively) [37,38]. Careful attention to local practice guidelines may optimize use of EEG monitoring and treatment of seizures. A study of 214 neonates demonstrated that even with access to conventional EEG monitoring, 7 of 74 neonates (9 percent) with seizures did not received antiseizure medication, and 27 of 139 neonates (19 percent) without seizures were treated with medication even after EEG was initiated [41]. Another study that leveraged clinical and administrative data for 20 North American neonatal intensive care units demonstrated that while 95 percent of neonates with EEG seizures were treated, 26 percent of those with concern for seizures but no EEG-confirmed seizures received antiseizure medication [42]. Thus, coordination of EEG review and detailed, regular communication with the bedside clinical team are necessary to ensure that infants with seizures are treated and those without seizures are not exposed to unnecessary medication.

A neonatal seizure is defined by the International League Against Epilepsy (ILAE) as "an electrographic event with a pattern characterized by sudden, repetitive, evolving stereotyped waveforms with a beginning and end. The duration is not defined but has to be sufficient to demonstrate evolution in frequency and morphology of the discharges and needs to be long enough to allow recognition of onset, evolution, and resolution of an abnormal discharge" [14]. This definition eliminates the previous requirement of 10-second minimum duration.

Seizures may or may not have a clinical manifestation.

●An "electroclinical seizure" occurs when the clinical event overlaps in time with an EEG-confirmed seizure.

●An "electrographic-only seizure" is an EEG-confirmed seizure without associated clinical signs.

●Clinical events that have no EEG correlate are not seizures.

Importantly, neonates who have high-risk clinical scenarios and clinical events that are very suspicious for seizures (eg, focal clonic jerking in a newborn with clinical concern for acute HIE) should be evaluated and treated urgently, even if EEG is not immediately available.

Video EEG monitoring — The gold standard for neonatal seizure diagnosis is multi-channel video continuous EEG (cEEG) monitoring [43]. Since this testing is specialized and resource-intensive, it should be reserved for newborns at highest risk for seizures. There are many examples of high-risk clinical scenarios, but in general cEEG monitoring should be considered for newborns with proven or suspected acute brain injury and comorbid encephalopathy, even if there are no clinical events suspicious for seizures. In an observational study, the probability of successful initial treatment for acute seizures was greater for 161 neonates who had cEEG monitoring for the indications of encephalopathy or pharmacologic paralysis (ie, a screening cEEG) compared with 353 neonates who had cEEG monitoring for the indication of suspected seizures (ie, a confirmatory cEEG) (39 versus 18 percent) [44].

A routine-length, 60-minute EEG is not considered sufficient to screen for neonatal seizures. For newborns at high risk of seizures, the American Clinical Neurophysiology Society recommends that video EEG monitoring be recorded for 24 hours [43]. In a prospective study of 426 consecutive neonates with clinically suspected seizures and/or electrographic seizures who underwent EEG monitoring (82 percent with confirmed electrographic seizures), the median time to electrographic seizure detection was seven hours from the onset of the recording [13].

If the interictal background is stable and no seizures are recorded after 24 hours, then monitoring may be discontinued. An exception is often made for neonates treated with therapeutic hypothermia for hypoxic ischemic encephalopathy (HIE). These infants are frequently monitored throughout cooling and rewarming due to the high incidence of seizures in this patient population (approximately 50 percent will have neonatal seizures) [43,45].

If seizures are identified, EEG monitoring should continue until the infant is seizure-free for 24 hours, unless this duration of monitoring is not in the infant’s best interests (eg, a newborn with seizures due to a severe brain malformation might not be expected to gain complete seizure control). Similarly, the guidelines specify that transfer to a different intensive care facility, solely for the purposes of EEG monitoring, might not always be in the infant’s best interest and should be considered on a case-by-case basis [43].

If EEG monitoring is initiated in order to evaluate whether discrete, abnormal paroxysmal events are seizures, then recording should continue until several events are captured. If the events are determined not to be seizures, then monitoring for that purpose may be discontinued.

Serial routine-length EEGs — When video-EEG monitoring is unavailable, routine-length EEG recording with simultaneous observation by clinicians or EEG technologists trained in the recognition and characterization of neonatal seizures is acceptable and can provide clinically important information.

Reduced-montage EEG — Another option is the limited-channel digital bedside EEG, which combines amplitude-integrated EEG (aEEG) with 1- or 2-channel EEG. aEEG should not be considered equivalent to conventional multi-channel video EEG, but it can be a useful adjuvant tool when video-EEG is not available [45].

While this technique is increasingly used in both term and preterm infants, there are important limitations [46,47]. Not all electrographic seizures are detected by this modality because of limited coverage of the scalp [48], low amplitudes, and slow frequency of typical seizures [49]. In addition, artifact in these unattended recordings with no simultaneous video recording can cause false-positive interpretations. The reported sensitivity and specificity varies between 25 and 80 percent, in part depending upon the experience of the reader [49,50] and the use of 1- versus 2-channel aEEG and the associated raw EEG tracings [51-54].

Despite these limitations, when standard EEG or continuous standard video-EEG recordings are not readily available, aEEG can be a useful tool; one study found that the use of aEEG improved clinical decision making and resulted in fewer neonates treated for seizures based solely on clinical findings [55].

The development of automated seizure detection systems holds promise for better and more widely available EEG monitoring in the future, but available systems are not yet sufficiently reliable [47,56-58].

ETIOLOGIC EVALUATION — If a diagnosis of neonatal seizures is being entertained, an expedited evaluation for the etiology is warranted (algorithm 1). Most neonatal seizures are provoked manifestations of acute brain injury and many require urgent, specific treatment. Therefore, the evaluation for an underlying etiology should occur in tandem with the diagnosis and treatment of seizures.

History — The history should attempt to identify risk factors for seizures and clues to the underlying etiology:

●Gestational and birth history – A thorough birth history should identify risk factors for anoxic injury such as nuchal cord or cord thrombosis, fetal heart rate decelerations, meconium, low Apgar scores, and placental abnormalities. The nature of the delivery is also important, as infants born by operative vaginal delivery are more likely to have intracranial hemorrhage. Other risk factors for birth injury include macrosomia, maternal obesity, and abnormal fetal presentation. (See "Neonatal birth injuries", section on 'Intracranial hemorrhage'.)

●Maternal history – Aspects of the maternal history that may be important include previous miscarriages (congenital anomalies), gestational diabetes (neonatal hypoglycemia), history of sexually transmitted diseases or other infections (neonatal transmission of infection), history of illness during pregnancy (eg, maternal rash and fever could suggest in utero viral infection), use of prescription or illegal substances (drug intoxication or withdrawal), and clotting or bleeding tendencies (neonatal stroke or hemorrhage).

●Family history – A detailed family history should include queries about early sibling death from unknown causes or consanguinity (inborn errors of metabolism) and family history of epilepsy, particularly neonatal (benign familial neonatal epilepsy).

Physical examination — Aspects of the physical examination may direct further testing and provide clues to the underlying etiology (table 5). The general examination should evaluate vital signs and assess for head size, birthmarks, somatic abnormalities or facial dysmorphisms, and any potential sign of infection (eg, bulging fontanelle to suggest meningitis, or rash to suggest TORCH infection).

The neurologic examination should include measurement of head circumference, assessment of mental status and level of alertness, cranial nerve exam, and motor exam to detect asymmetry in spontaneous movements or abnormal tone that may suggest a structural brain lesion or neonatal encephalopathy.

The typical presentation of an inborn error of metabolism usually includes poor feeding, lethargy, and respiratory distress after an initial symptom-free period of several days. Some infants may present with isolated seizures, however. Seizure characteristics that may suggest an underlying metabolic defect include myoclonic seizure semiology and seizures that are refractory to conventional treatment. (See "Etiology and prognosis of neonatal seizures", section on 'Inborn errors of metabolism'.)

Laboratories — Suggested laboratory tests are presented in the table (table 6). Signs and symptoms of systemic and central nervous system (CNS) infection can be subtle and nonspecific in newborns. If infection is suspected, appropriate cultures should be drawn and treatment initiated, including antibiotics at meningeal doses and acyclovir for herpes simplex virus in the appropriate clinical scenario.

Lumbar puncture is recommended in all neonates with a positive blood culture and should also be considered whenever there is clinical suspicion for sepsis, since clinical signs of CNS infection can be lacking in young infants and infection is among the most common causes of neonatal seizures. (See "Clinical features, evaluation, and diagnosis of sepsis in term and late preterm neonates", section on 'Laboratory tests'.)

If infection is not suspected, lumbar puncture is typically reserved for cases of refractory or recurrent seizures without a clear etiology on initial evaluation and structural imaging. In that instance, the lumbar puncture is performed to assess for metabolic disorders.

Neuroimaging — Magnetic resonance imaging (MRI) is the preferred imaging modality and should be performed in all neonates with seizures to evaluate for and evidence of hypoxic-ischemic injury, intracranial hemorrhage, ischemic stroke, or brain malformations (algorithm 1). In addition to routine sequences, magnetic resonance (MR) angiography should be obtained if arterial ischemic stroke or vascular malformation are suspected. MR venography is indicated to evaluate for venous sinus thrombosis; this is particularly important in full term infants. MR spectroscopy can be performed where available to evaluate for certain metabolites such as glycine (nonketotic hyperglycinemia), lactate (mitochondrial disorders), or loss of creatine (disorder of brain creatine metabolism).

In a single-center prospective study of 77 infants with neonatal seizures, MRI was abnormal in 45 out of 70 infants imaged (64 percent). The most common findings were white matter abnormalities (19 percent), focal cortical abnormalities (14 percent), abnormal deep gray nuclei (13 percent), and multifocal or diffuse cortical abnormalities (11 percent) [59]. Isolated subdural or extradural hemorrhage was present in five cases. In nine cases, the diagnosis was made by MRI, as all other investigations were normal or nonspecific.

If an infant is not clinically stable for MRI, or if there is an anticipated delay in obtaining MRI, cranial ultrasound should be performed to evaluate for intracranial hemorrhage or hydrocephalus. Ultrasound has the advantage of being noninvasive and can be performed at the bedside. Ultrasound has high sensitivity and specificity for locating hemorrhages and defining ventricular size. (See "Clinical features, diagnosis, and treatment of neonatal encephalopathy", section on 'Cranial ultrasound'.)

Computed tomography (CT) should generally be avoided in young children, especially neonates, since MRI provides superior resolution and does not involve exposure to ionizing radiation [43,45].

Genetic testing — The role of genetic testing in the clinical care of children with epilepsy is evolving as the number of monogenetic causes of early epileptic encephalopathy increases and specific treatments become available for some syndromes. In a prospective cohort study of 611 consecutive newborns with seizures, 13 percent had an epilepsy syndrome, including 35 infants (6 percent) with epileptic encephalopathy and 32 with congenital brain malformations [15]. Among 29 neonates with epileptic encephalopathy who underwent genetic testing, 83 percent had a genetic etiology identified, most commonly KCNQ2 encephalopathy. Among 23 neonates with brain malformations, 7 had a putative genetic etiology. (See "Overview of neonatal epilepsy syndromes" and "Focal epilepsy: Causes and clinical features", section on 'Genetic focal epilepsy syndromes'.)

In addition to treatment implications (eg, preferential use of sodium channel-blocking antiseizure medications in KCNQ2 developmental and epileptic encephalopathy, avoidance of these medications in Dravet syndrome due to pathogenic variants in SCN1A), identification of a genetic etiology assists in prognosis and genetic counseling and avoids further extensive etiologic testing [60,61]. Emerging evidence also suggests that early genetic testing may decrease hospital length of stay [62]. (See "Dravet syndrome: Management and prognosis" and "Overview of neonatal epilepsy syndromes", section on 'KCNQ2-DEE'.)

Genetic testing should therefore be strongly considered in neonates with epilepsy who do not have an acute provoked cause identified on initial history, examination, and neuroimaging. When genetic testing is performed, we suggest using a gene panel for epileptic encephalopathies and brain malformations, or whole exome sequencing, rather than serial testing of single genes. Given the phenotypic overlap of various genetic epilepsies, testing for multiple different mutations at the same time is more practical and cost efficient than testing for one mutation at a time. Specific information on genetic testing is available at https://www.ncbi.nlm.nih.gov/gtr/. Counseling for genetic testing is discussed separately. (See "Genetic testing".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

SUMMARY AND RECOMMENDATIONS

●Seizures as manifestation of a CNS disorder – Neonatal seizures may be the first, and perhaps the only, clinical sign of a central nervous system (CNS) disorder in the newborn infant. As such, seizures may indicate the presence of a potentially treatable etiology and should prompt an immediate evaluation to determine cause and to institute etiology-specific therapy. (See 'Etiology' above.)

●Clinical features – Seizures in the neonate have unique clinical features when compared with those of older infants and children. The most common clinically apparent seizure types in neonates are focal clonic, focal tonic, some types of myoclonic, and epileptic spasms (table 3), but most neonatal seizures are electrographic-only. (See 'Clinical features' above.)

●Electrographic-only seizures – Electrographic-only (ie, subclinical) seizures occur without clinical manifestations and are very common in the neonate. These seizures have similar pathogenesis and similar prognostic and treatment implications compared with electroclinical seizures. (See 'Electrographic-only seizures' above.)

●Differential diagnosis – Neonatal seizures must be differentiated from nonepileptic paroxysmal events and nonseizure behaviors of the newborn, and EEG is often required to distinguish between them. Bedside clinical observation is inadequate for accurate neonatal seizure diagnosis. (See 'Differential diagnosis' above and "Nonepileptic paroxysmal disorders in infancy".)

●Evaluation and diagnosis – The diagnosis of neonatal seizures is based upon clinical observation combined with EEG monitoring (algorithm 1). The diagnostic evaluation of a neonate with suspected seizures has several objectives, including clinical characterization of the events, determination of whether the episodes are seizures or nonseizure events, and identification of an underlying etiology. (See 'Diagnosis' above and 'Etiologic evaluation' above.)

●EEG – Continuous video-EEG (cEEG) is the gold standard for diagnosis and quantification of seizures in neonates. cEEG monitoring should be targeted at newborns with proven or suspected brain injury and comorbid encephalopathy. When cEEG monitoring is not available, serial routine-length EEGs or continuous amplitude-integrated EEGs may be used as adjuvant diagnostic tools. (See 'Video EEG monitoring' above.)

●Role of genetic testing – Neonatal epilepsies most often have identifiable genetic etiologies. Genetic testing should be strongly considered in neonates with seizures who do not have an acute provoked seizure cause identified on initial history, examination, and neuroimaging; these infants usually have epilepsy. When genetic testing is performed, we suggest using a gene panel for epileptic encephalopathies and brain malformations, or whole exome sequencing, rather than serial testing of single genes. (See 'Genetic testing' above.)