Definition
A clinical seizure is defined as a paroxysmal alteration of neurologic function (behavioral, motor and/or autonomic).
An electrographic seizure is defined as a repetitive discharge that evolves in time and space. In practical terms, it is a seizure detected only by electroencephalogram (EEG) without clinical correlate.
An electroclinical seizure is an event with concomitant clinical and electrographic seizures.
Incidence
The incidence of seizures in the term neonate ranges between 1 and 3/1000 live births.
Higher incidence is observed among neonates with low gestational age and low birthweight—up to 57.5/1000 for infants <1500 g and 20.4/1000 for infants <28 weeks.
The neonatal period has the highest incidence of seizures across the life span.
Pathophysiology
The immature brain is highly excitable.
The balance between excitation and inhibition favors excitation.
The neurotransmitter receptors are developmentally regulated with lower expression of inhibitory receptors (some γ-aminobutyric-acid or GABA receptors) and higher expression of excitatory receptors (glutamate receptors) compared to adulthood.
GABAA receptor activation in the immature brain can cause depolarization instead of hyperpolarization because the chloride gradient is reversed in the immature brain.
Developmental regulation of ion channels and neuropeptides may also contribute to neuroexcitation.
The neonatal brain is a unique environment that likely explains, at least in part, the refractoriness to common antiepileptic medications.
Etiology
See Table 39-1.
Etiology based on seizure onset
First 6 hours after birth
NKH, sulfite oxidase/molybdenum cofactor deficiency, B6/PLP dependent seizures, cortical dysplasia, trauma, local anesthetic toxicity
After first 6 hours
HIE, cortical dysplasias, vascular, trauma, infectious, metabolic, toxic
Risk factors
Family history of neonatal seizures
Benign familial neonatal seizures (BFN): KCNQ1, KCNQ2, KCNQ3 (Note: Some mutations can be associated with a malignant course, and not benign as previously thought.)
Sodium channelopathies: SCN1A, SCN2A
Metabolic disorders
Problems with pregnancy
Fever and/or rash during pregnancy
Congenital infection (SCRATCHES: syphilis, CMV, rubella, AIDS, toxoplasmosis, chicken pox, HSV, enterovirus)
Chorioamnionitis
History of vaginal bleeding
Abruption, previa
Hiccups/increased fetal movement
NKH (nonketotic hyperglycinemia), B6/PLP (vitamin B6/pyridoxal-5-phosphate) dependent seizures, cortical dysplasia
Substance abuse
Cocaine
HELLP syndrome
Fatty acid oxidation disorders
Problems with delivery
Fetal heart rate abnormalities, prolapsed cord, placenta abruption, previa
Hypoxic-ischemic encephalopathy (HIE)
No maternal pain relieve, pupillary abnormalities, cardiac arrhythmia
Local anesthetic toxicity
Precipitous delivery, vacuum, breech
Subdural, subarachnoid and intraparenchymal hemorrhages, stroke
No vitamin K administration at birth
Hemorrhagic disease of the newborn
Maternal fever and abnormal amniotic fluid
Chorioamnionitis
Premature delivery/extremely low birthweight infants
Higher risk of intraventricular hemorrhage (IVH), sepsis, and meningitis
Clinical presentation
Clinical assessment of a suspected seizure (paroxysmal alteration of neurologic function) should include
Mental status: Most seizures course with altered mental status.
Spontaneous character of the event: Seizures are characteristically unprovoked and should not respond to restrain, change in position or stimulation.
Vital signs: Most seizures occur with tachycardia.
Clinical seizures types
Subtle seizures
Paroxysmal alterations in neonatal behavior and motor or autonomic function (tachycardia, blood pressure elevation, apnea, cutaneous vasomotor phenomena, pupillary change, salivation, or drooling) that are not clearly tonic, clonic, or myoclonic.
Sustained eye opening with ocular fixation or horizontal gaze deviation appear to be the most common manifestation in preterm and term neonates, respectively.
Chewing, pedaling motions, and autonomic phenomena can also be seen.
Isolated apnea is an uncommon seizure manifestation but it may represent a seizure when associated with other symptoms such as ocular phenomena or mouth movements. The more common association with tachycardia rather than bradycardia helps in the differential with apnea of prematurity (unless the seizure is prolonged).
Clonic seizures
Characterized by slow rhythmic movements of the extremities (one to three jerks per second) and may be focal or multifocal.
Generalized clonic seizures are rare in neonates given that the white matter is not fully developed.
Tonic seizures
Consists of flexor or extensor sustained posturing and may be focal or generalized.
Myoclonic seizures
Faster jerks when compared with clonic seizures and have a predilection for flexor muscle groups.
They can be focal, multifocal, or generalized.
Seizure types and correlation with EEG changes
Among subtle seizures, ocular manifestations are more commonly associated with concomitant EEG seizure activity but other subtle manifestations are less likely associated with electrical discharges.
Clonic seizures are the most consistently associated with rhythmic EEG discharges, making diagnosis more certain.
Tonic and myoclonic seizures may or may not be associated with EEG seizure activity.
Caution should be made in attributing clinical manifestations without electrical EEG abnormalities to seizures, although it is important to keep in mind that a normal ictal EEG does not exclude an epileptic seizure given that a scalp EEG may fail to detect a deep seizure focus in the brain.
When in doubt about the epileptic nature of certain manifestations, it is important to look for other coexisting seizure manifestations, evaluate the seizure risk, and pursue a thorough evaluation. Prolonged EEG monitoring may be indicated.
Nonepileptic paroxysmal events
It is important to recognize common nonepileptic paroxysmal events that can mimic neonatal seizures.
Jitteriness is characterized by movements with qualities primarily of tremulousness but occasionally of clonus. Clinical assessment is key given that jitteriness is exquisitely stimulus sensitive, the movements are tremor quality and not clonic, tend to cease with passive flexion, and there are not associated with abnormal ocular phenomena or autonomic discharges.
Sleep myoclonus is characterized by myoclonic jerks during sleep. They can range from mild to multiple violent jerks and may not respond to restrain or change in position.
Normal neonatal motor activity includes roving eye movements, intermittent gaze dysconjugation, occasional nystagmus jerks, and isolated generalized myoclonic jerk at awakening.
Clinical cues suggestive of certain disorders
Skin vesicles: HSV, incontinentia pigmenti (IP)
Skin, hair, and nails abnormalities: Neurocutaneous syndromes (tuberous sclerosis, IP)
Retinopathy: SCRATCHES
Tonic/myoclonic seizures: Early infantile epileptic encephalopathy (EIEE), early myoclonic encephalopathy (EME)
Stimulus sensitive: NKH
Encephalopathy: Metabolic, EME, EIEE, HIE, hemorrhage, infection
Hepatomegaly: Congenital infections, metabolic disorders
Dysmorphic features: Developmental anomalies, metabolic disorders
Prematurity: IVH, venous thrombosis
Dehydration, poor feeding, infection
Suspicion of CNS infection without CSF pleocytosis: Parechovirus encephalitis
Diagnosis
Clinical diagnosis (see Sections E.1 and E.2).
An EEG should be obtained to confirm electroclinical seizures given that the clinical symptoms may be very subtle and difficult to detect.
Evaluation
Seizures are many times the first indicator of central nervous system dysfunction in the neonate; prompt evaluation in order to establish an etiology is warranted.
Laboratory evaluation (Figure 39-1)
EEG: Certain EEG patterns are helpful hints for seizure etiology (Figure 39-2)
Imaging (MRI): Characteristic MRI findings of certain disorders (Figure 39-3)
Management
Correct electrolytes abnormalities
Glucose, sodium, magnesium, and calcium.
In the absence of other coexisting causes for seizures, no antiepileptic medications are required.
Pharmacological agents
There is large variability regarding the pharmacological protocol for neonatal seizures among centers. A similar serial approach is commonly used in many centers.
Phenobarbital
Loading dose 40 mg/kg (20 to 40 mg/kg).
Maintenance dose 3 to 5 mg/kg/d (qd or divided bid).
Lorazepam or midazolam (monitor cardiorespiratory function; note possible paradoxical excitation/tremor)
Lorazepam 0.05 to 0.1 mg/kg/dose.
Midazolam 0.15 mg/kg load, immediately followed by continuous infusion at 1 μg/kg/min (infusion can be increased by 0.5 to 1 μg/kg/min every 2 minutes until a favorable response or a maximum of 18 μg/kg/min). If seizures persist after the initial bolus/infusion, a second bolus of 0.10 to 0.15 mg/kg can be administered after 15 to 30 minutes.
Phenytoin or fosphenytoin
Loading dose 20 mg/kg (can be repeated 5 mg/kg dose).
Maintenance doses 3 to 5 mg/kg/d in two to four divided doses.
Lidocaine
4 mg/kg bolus over 20 minutes followed by an infusion of 2 mg/kg/h (monitor for possible cardiotoxicity).
Levetiracetam
Small clinical trials suggest levetiracetam is safe and higher doses than used in older children are necessary to maintain desirable levels (NCT01239212, NCT01261416, NCT00884052 and NCT00461409). An efficacy trial is currently active (NCT01475656).
A trial of pyridoxine is warranted in refractory neonatal seizures without a known cause (100 mg/kg dose IV, monitor for possible apnea as a rare but possible side effect) or pyridoxal-5-phosphate (30 to 60 mg/kg/d in divided doses daily, no IV form is available in the United States).
Bumetanide is being used as part of a clinical trial (NCT00830531).
Other agents have been used and anecdotally found to be effective including topiramate and oxcarbamazepine but no safety or efficacy data are available. The fact that seizures often stop at 4 to 5 days, should be considered when assessing the efficacy of add on therapies.
Monitor antiepileptic levels
Phenobarbital goal 20 to 40 mg/L.
Phenytoin goal 15 to 25 mg/L (2.5 to 3 mg/L unbound).
Efficacy of antiepileptic medications in the neonatal period
Phenobarbital and phenytoin were reported to be equally but incompletely effective as anticonvulsants in the neonatal period (43% for phenobarbital, 45% for phenytoin, and 57% for combined treatment).
Another randomized study focused on a second agent for neonatal seizures after phenobarbital 40 mg/kg and showed that midazolam and clonazepam were both inefficacious controlling seizures; there was a suggestion that lidocaine may decrease seizure burden but it did not affect outcome.
A posterior retrospective nonrandomized study suggested rapid seizure control of status epilepticus using midazolam infusion in patients who had failed phenobarbital and phenytoin treatment.
Treatment of subclinical seizures
Although most centers will treat subclinical seizures (electrographic seizures not accompanied by clinical symptoms), it remains controversial if treating subclinical seizures will affect outcome.
EEG follow-up
If clinical seizures are detected and antiepileptic medications are started, an EEG is routinely performed in 24 hours to monitor possible subclinical seizures.
If the EEG is abnormal with multiple seizures, a continuous-video EEG is commonly performed until seizures are controlled or stabilized.
Duration of antiepileptic medications
There is no uniform recommendation for stopping antiepileptic medications.
In HIE cases, seizures usually stop after 72 to 96 hours and antiepileptic medications are commonly stopped 1 to 4 weeks after last seizure.
In general, neonates with severe seizures and brain abnormalities are more likely to remain on antiepileptic medications for longer periods of time but neonates with mild seizures are more likely to be able to be taken off antiepileptic medications within 1 to 4 weeks.
Seizures and hypothermia
Amplitude integrated EEG is commonly used to monitor seizures when neonates undergo hypothermia after HIE.
The effect of hypothermia on the incidence or severity of neonatal seizures is yet to be determined.
Initial studies indicate that seizure burden is lower in hypothermia but confirmatory studies are needed.
Early developmental/therapeutic interventions
Inpatient consult for physical therapy should be considered, especially when an underlying brain injury (HIE, IVH) is the cause for seizure development.
Referral to early intervention should be offered to all neonates at risk for neurologic deficits.
Prognosis (Table 39-2)
There is evidence supporting the association of neonatal seizures with adverse neurodevelopmental outcome; however, no significant relationship has been found between neurodevelopmental outcome and response to antiepileptic therapy using phenobarbital and/or phenytoin.
Discharge
Teaching
Parents should be educated about their child’s current condition and comorbidities acquired during their NICU stay, as well as expected and possible outcomes.
Parents should be instructed how to give medications prescribed at discharge and told what condition they are treating. They should understand that if the symptoms worsen (muscle tone, seizures, etc) postdischarge that the medicine may need to be weight adjusted. They should also understand route to be given (PR, GT) in emergent situations such as a prolonged seizure.
Parents should meet with a physical therapist and learn stretching/strengthening exercises applicable to their child. Also, consider teaching the parents infant massage if the child is hypertonic or very irritable.
Parents should meet with a speech/occupational therapist prior to discharge if the child has a history of feeding difficulties.
If the facilities are available, consider having the parents room-in with their baby prior to discharge.
Monitoring
Consider home apnea monitor for infants with persistent apnea and bradycardia spells related to poorly controlled seizure disorder.
Infants with severe brain injury should demonstrate stable temperature regulation, without an external heat source, for several days prior to discharge.
Safety
Caregivers should be instructed in infant CPR.
Infants should have a car seat safety test for at least 90 minutes prior to discharge. Infants with poor head control at discharge may need to use the manufacturer’s insert to provide lateral head support.
An emergency plan should be established, instructing what to do (give rectal diazepam, call PCP, call neurologist, call 911, etc) if the child has a prolonged seizure and what medical facility to bring them to.
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