Neonatal seizures

OVERVIEW: What every practitioner needs to know

Are you sure your patient has neonatal seizures? What are the typical findings for this disease?

Seizures are episodic, unexpected, sudden events which result from an excessive activity of neurons in the brain. In neonates, seizures can often be subtle and easily missed by healthcare professionals. In addition, there is no clear classification system for neonatal seizures as they are often subtle and not the typical generalized seizures seen in older children.

Seizures can present with subtle findings in neonates such as eye deviation to one side, lip smacking, staring, pedaling of the feet, apnea and tongue movements, especially preterm infants. More typical presentations are clonic (rhythmical jerking) or tonic (stiffening) motion of the arms or legs. Clonic seizures are more common in term infants. Tonic seizures can be seen in both preterm and term infants. As infants do not complete myelination until a later age, neonates may have partial seizures where the seizure arises from one area of the brain and spreads locally. Generalized seizures often do not occur until later in infancy.

Myoclonic seizures are represented by a rapid jerk of the extremities and trunk.They can be in one extremity or migrate (multifocal myoclonic seizures). A common etiology is hypoxic ischemic encephalopathy.

Seizures can also be silent (electrographical or subclinical); the baby can be asleep or have no clinical signs.This requires an electroencephalogram (EEG). Healthcare professionals should have a high degree of suspicion in neonates, especially those with a history of status epilepticus. A recent study found that only a third of the seizures showed overt clinical signs. Furthermore, neonates often have uncoupled subclinical/electrographical seizures after a clinical seizure has stopped. Scher (2003) studying 59 premature and full-term babies found that 58% had subclinical seizures uncoupled from the clinical event after 24 hours of anti-seizure medication administration.

Epilepsy and status epilepticus


Epilepsy is the result of recurrent (more than 2-3), unprovoked seizures usually from a structural or genetic propensity. In neonates, there is a tendency for patients to have seizures easily, often provoked from metabolic derangements and sepsis. In addition, most seizures occur within a period of a couple of days and do not occur later in life. Therefore, most neonates do not have "neonatal epilepsy." Seizures occur in approximately 1 to 5 per 1000 live births, making seizure one of the most common consults for a neonatal neurocritical care service. Eighty percent of neonatal seizures start in the first week.

Definition of status epilepticus in neonates:

Status epilepticus is defined as a continuous seizure lasting more than 30 minutes. It can also be the sum of smaller individual seizures with no resolution to baseline neurological status where the activity exceeds 50% of a one hour tracing on an EEG. This is considered a neurological emergency as there is usually higher morbidity and mortality. Unfortunately, there is no clear consensus in terms of the exact definition for neonatal status epilepticus. If one is to use the definition of status epilepticus as defined above, then status epilepticus has higher morbidity and mortality rates in neonates than in older children. It is unclear if morbidity is related to the prolonged seizure or to the underlying cause of the seizure.

What other disease/condition shares some of these symptoms?

There are multiple conditions that can be confused with seizures. Jitteriness may be due to neonatal withdrawal from maternal prenatal drugs. They may also be due to hypocalcemia. Jitteriness is not associated with eye deviation or autonomic symptoms. If these are seen, seizures should be suspected. If the tremor stops when the limb is restrained, a seizure is unlikely.

Apnea shares similar symptoms with seizures and is frequent in premature infants. Apnea associated with a seizure is usually associated with other symptoms such as stiffening or clonus, although it may rarely occur in isolation. Isolated stiffening of respiratory muscles causes cessation of breathing and can lead to cyanosis; this will be identified as apnea on a cardiorespiratory monitor. Seizures are ordinarily accompanied by tachycardia whereas apnea of prematurity is associated with bradycardia. However, if hypertonus of respiratory muscles is severe enough to cause prolonged cyanosis, bradycardia will occur instead.

Normal baby/neonatal movements can be also confused with subtle seizures. An example is a Moro or startle reflex, which is commonly noted in babies until 2 months of age. Abnormal baby movements that may resemble neonatal seizures include opisthotonus, dystonia, or chorea associated with inborn errors of metabolism or gastroesophageal reflux provoking Sandifer's syndrome, which is a reaction to pain from the reflux and is manifested by stiffening and arching of the back

Myoclonus may look like myoclonic seizures and maybe be either benign or pathological. An example is benign neonatal sleep myoclonus, which occurs during sleep and is normal in babies with a normal neurological exam. Myoclonus is not associated with changes on EEG. Pathological myoclonus is often associated with hypoxic ischemic encephalopathy or after weaning of a sedative medication. The infants often have an abnormal neurological examination. The EEG may not show electrographic changes during the jerk, but background EEG activity may show discontinuity or low amplitude.

Exaggerated startle reflex or hyperekplexia is another type of movement that can be confused with neonatal seizures and are seen in disorders such as stiff baby syndrome. Stiff baby syndrome is an automatic dominant genetic disorder with stiffness throughout the body, exaggerated reflexes and motor delay later in life.

What caused this disease to develop at this time?

Neonatal seizures have numerous causes. They include:

  • Infections such as meningitis, sepsis or intrauterine infection/TORCH, maternal drug effect

  • Intraventricular hemorrhage or stroke

  • Birth trauma

  • Hypoxic ischemic encephalopathy

  • Neurocutaneous disorders such as tuberous sclerosis or incontinentia pigmenti

  • Cortical malformations for example: hemimegalencephaly, lissencephaly, polymicrogyria or cortical dysplasia

  • Metabolic derangements such as kericterus, hypoglycemia, uremia, hypomagnesemia, or parathyroid problems/hypocalcemia

  • Genetic disorders (i.e., benign familial neonatal seizures and benign idiopathic neonatal seizures ["5th day fits"])

(Benign familial neonatal seizures occur in the first 2-3 days of life with patients having normal development. Patients outgrow their seizures at 2-6 months of age. Benign idiopathic neonatal seizures are seen on the first week of life and are called "5th day fits" as they are often noted on to start on the 5th day. Usually the seizures remit by the first month of age.)

  • Metabolic diseases such as pyridoxine deficiency, glycine encephalopathy, glycogen synthetase deficiency, urea cycle defects, mitochondrial diseases, maple syrup urine disease, ketotic hyperglycemia, Gauchers, GM1 gangliosidosis type I, neonatal adrenoleukodystrophy, proprionic academia, or methylmalonic academia.

A history and physical examination can help narrow the differential diagnosis. Important historical facts include whether a patient is preterm or full term, as some etiologies are more common in preterm infants; for example, germinal matrix and intraventricular hemorrhages occur more frequently in preterm infants. Other historical points include whether there is worsening of symptoms after starting enteral feedings. This is compatible with an inborn error of metabolism.

A history of fetal distress or difficulties with delivery with low Apgar scores suggest hypoxic-ischemic encephalopathy or birth trauma. A history of the mother being exposed to cat feces or raw meat supports the possibility of toxoplasmosis. A history of maternal chorioamnionitis suggests the possibility of neonatal septicemia with meningitis. Family history of seizures suggests familial neonatal seizures or benign idiopathic neonatal seizures.

Physical examination findings are helpful. In most neonates with seizures, the neurological examination will be normal. Skin stigmata can be seen in neurocutaneous disorders. Hemiparesis suggests an intracranial hemorrhage or stroke. Hiccups are more common in nonketotic hyperglycinemia. Neonates with seizures associated with subarachnoid hemorrhage may be irritable, but are otherwise well. Lethargy or coma in a child with a normal birth history suggests metabolic disease. Temperature instability (too low or too high) suggests septicemia. Eye findings may help to suggest cytomegalovirus (CMV) or some disorder of inborn error of metabolism.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

An electroencephalogram (EEG) is helpful to determine if a seizure is present and if seizures progress to status epilepticus. Often neonates will have subclinical or electrographical seizures that are uncoupled from the clinical seizure. Without an EEG, it may be difficult to differentiate subtle seizures from normal myoclonic jerks or jitteriness.

The EEG needs to be read by a neurologist with training in neonatal EEGs, preferably by a pediatric epileptologist, as many EEG waveforms might be overcalled by adult neurologists. A neonatal electrographic seizure is a sudden, repetitive, progressing pattern noted on EEG with an amplitude of at least 2 microvolts and minimum duration of 10 seconds. An EEG may also have specific patterns that can help to determine the etiology such as burst suppression seen in Otahara's syndrome or theta pointu alternants noted in benign idiopathic neonatal seizures. In addition, an EEG can help to determine prognosis. Seizure activity superimposed on a normal background is associated with a better outcome than seizures on a slow, invariant and undifferentiated background.

Amplitude integrated EEG (aiEEG) may be helpful in determining if a patient has seizures. However, it may also miss many seizures as it employs only a few electrodes often placed by inexperienced personnel. In addition, false positives may arise from electrode artifacts. Seizures identified with aiEEG should be verified by a formal multichannel neonatal EEG.

A comprehensive chemistry panel is helpful to investigate a metabolic reason for seizures such as hypoglycemia, hypocalcemia, hypomagnesemia and uremia. Extreme elevations of bilirubin suggest kernicterus and evidence of liver and kidney damage in an infant with obtundation and seizures suggests hypoxic ischemic encephalopathy.

Lumbar puncture may be needed to obtain CSF to look for evidence of bacterial or viral meningitis or encephalitis. TORCH titers for toxoplasmosis, rubella, cytomegalovirus and herpes may be helpful. CSF is also needed to look for low glucose (glucose transporter deficiency), glycine (nonketotic hyperglycinemia), neurotransmitters (neurotransmitter deficiency) or lactate and glucose (mitochondrial disease). There will be higher glycine levels in the CSF compared to plasma in nonketotic hyperglycinemia.

Pyridoxine challenge with injection of 100mg of pyridoxine IV along with a concurrent EEG is essential to rule out a pyridoxine deficiency as there is no other means of making a rapid diagnosis. If the EEG normalizes within 5 minutes (although some reports state that it can be hours), pyridoxine deficiency or dependence is likely. If pyridoxine is injected, the patient should be on a cardiac respiratory monitor to monitor for any arrhythmias. Measurement of a nonspecific marker such as pipecolic acid or alpha aminoadipic semialdehyde in serum and CSF is available for confirmation. Genetic testing for ALDH7A1, the gene marker for pyridoxine deficient seizures, is also available commercially.

Biochemical markers for benign idiopathic neonatal seizures (KCNQ2 or KCNQ3) are also available in serum and can confirm the diagnosis.

Would imaging studies be helpful? If so, which ones?

Cranial magnetic resonance imaging (MRI) is preferable. This will give more detailed information about brain parenchyma and help to rule out a cortical malformation, stroke or other structural reasons for seizures. A computed tomography (CT) scan involves radiation and provides less detail. However, it is also easier to obtain, requires less sedation and is less expensive. CT may identify calcifications in tuberous sclerosis or TORCH infections which may be missed on MRI. Except in cases of intracranial hemorrhage a cranial ultrasound is seldom helpful. A recent study looked at the use of MRI scanning and found that an etiology could be detected with this method in 95% of cases of neonatal seizures.

Confirming the diagnosis

The first important step is to watch the event see whether it is provoked by position and to determine the state of consciousness (i.e., is the child sleeping?). If movements disappear with restraint or when the baby is distracted, it is less likely to be a seizure.

A history and physical examination is also essential for diagnosis.

The next step would be to order an electroencephalogram (EEG) to confirm the diagnosis. There have been several studies showing the importance of a bedside overnight EEG monitor to determine whether there is any subclinical seizures or subtle clinical seizures that are easily overlooked. An EEG showing electrographical seizures should prompt further workup to determine etiology which may include an MRI scan and lumbar puncture. A genetics/ metabolic consult should be considered in cases where the patient has other systemic involvement or dysmorphic features.

If you are able to confirm that the patient has neonatal seizures, what treatment should be initiated?

Firstly, IV correction of any metabolic derangement is necessary. An EEG should be initiated to insure that the patient is actually seizing and to monitor the course of treatment to rule out any subclinical seizures. In addition, IV access and starting fluids is mandatory along with maintaining an airway. If a metabolic disease is suspected, stop the regular diet and consult with a genetics/metabolics physician.

There is no clear consensus among epileptologists as to what medications work in neonatal seizures and no standard protocol among neurologists. Few randomized drug trials are available in this specific population. Epileptologists are concerned that standard medications may not be neuroprotective and may impair later cognition. However, common treatments will be listed here:

The medication usually given at first presentation of seizures is a benzodiazepine such as lorazepam at 0.1 mg/kg/dose. Another option is diazepam at 0.5 mg/kg/dose. However, benzodiazepine half-life is short and seizures may recur. They also cause sedation, making neurological assessment difficult.

If first line medication is ineffective, phenobarbital at a loading dose of 20 mg/kg/dose is often given with a maintenance dose of 3-5 mg/kg/day divided twice a day. This will also cause sedation and may depress respiration if combined with a benzodiazepine. Long term, there are concerns about cognition. Serum levels of 20-30 microgram/mL are usually considered therapeutic. Some epileptologists have raised concentrations to 50-70 microgram/mL using repeated doses of 10 mg/kg to 40 mg/kg although this approach is associated with respiratory depression and sedation.

If phenobarbital does not stop the seizures, most will administer fosphenytoin or phenytoin at a loading dose of 20 mg/kg with maintenance dosing at 5-10 mg/kg/day. Serum levels are often hard to maintain in neonates. Therefore frequent levels should be obtained with a goal of 15-20 microgram/mL. Levels higher than 30 microgram/mL can paradoxically worsen seizures. It is important to monitor cardiac rhythm and blood pressure as phenytoin can be cardiotoxic at high rates of infusion.

Fosphenytoin is more expensive, but hypotension and arrhythmias are less frequent. One study comparing phenobarbital and phenytoin found that they controlled seizures in 43%-45% of neonates when used alone, but if used together efficacy increased to 60%.

If none of these stop seizures, alternatives are available, although dosing and efficacy are unclear. Information is based on small samples of neonates or extrapolated from adult data. Valproic acid should be avoided as this is associated with liver toxicity, especially in neonates. Some treatments that have been reported in case studies as helpful for neonatal seizures include levetiracetam, which comes in intravenous format and has no significant systemic issues; topiramate, which has been seen in some rodent studies to potentially have a neuroprotective effect but is only available through capsule or pills; lidocaine, although there is some concern regarding the cardiovascular adverse effects; and ketogenic diet, although ketosis is difficult to induce in neonates. Medications such as bumetanide, which is still being studied, may be helpful in the future. For refractory neonatal status epilepticus, there is widespread use among pediatric neurologists of midazolam continuous infusion, which has been helpful anecdotally. Unfortunately, there are no randomized, controlled medical studies showing treatment options outside of phenobarbital, short-term benzodiazepines, and phenytoin/fosphenytoin.

Long-term management occurs at an outpatient neurology visit. Unfortunately, there is no consensus among neurologists as to how long to treat. Most seizures resolve during the NICU course and do not require chronic medication at discharge. This is especially true if seizures are caused by transient metabolic derangements or sepsis and the neonate has a normal neurological exam. We usually continue a medication for 2-3 weeks after the last seizure and then wean off prior to discharge.

On the other hand, patients with status epilepticus, subclinical seizures or breakthrough clinical seizures or those who have abnormal neurological exams or etiologies such as hypoxic ischemic encephalopathy, metabolic illness or cortical dysplasias may require home dosing of phenobarbital or other medication. Usually, anticonvulsants are continued for 6 months and then weaned off if the patient is seizure free.

Some may still continue maintenance medication in the presence of cortical dysplasia, hypoxic ischemic encephalopathy or a neurocutaneous disorder where the likelihood of continued seizures is high. The goal on discharge is to limit medication to monotherapy. Fosphenytoin/phenytoin maintenance is rare because blood levels are hard to maintain and administration is associated with facial changes and gum hypertrophy. If a child requires treatment past 3-6 months, most neurologists will use carbamazepine, levetiracetam or topiramate rather than phenobarbital due to the long-term issues with behavior and cognition on pnenobarbital.

What are the adverse effects associated with each treatment option?

Clinically, there has been studies suggest that phenobarbital is associated with cognitive problems, osteopenia and drowsiness or irritability if used long term. Phenytoin is associated with gum hypertrophy, hirustism, facial coarsening, and osteopenia. Unfortunately, not enough research is currently available to see which of the medications are effective with the least adverse effects.

What are the possible outcomes of neonatal seizures?

The outcome for neonatal seizures depends on the etiology. With metabolic derangements, subarachnoid hemorrhage and sepsis, the prognosis is good, especially if EEG background is normal and the neurological examination is normal.

With hypoxic ischemic encephalopathy, stroke/intraventricular hemorrhage, cortical malformation, neurocutaneous disorders, certain types of encephalitis or TORCH infections and inborn errors of metabolism, the prognosis is more guarded with possible future seizures or impaired neurodevelopment. This is especially true if the patient has a poor EEG background, status epilepticus or spikes in the EEG background, has required multiple anticonvulsants to control seizures or if the neurological examination or MRI is abnormal. A study of 82 such infants found that 27% developed epilepsy, 25% had cerebral palsy, 20% had mental retardation and 27% had learning disorders. In a recent literature survey, 17.9% of neonatal seizure patients developed epilepsy, most within the first year of life; 80.7% of these patients have other neurological impairments.

For patients with a poor prognosis, providers should be ready to discuss chronic anticonvulsant therapy for seizures and need for an intensive developmental therapy program along with issues with mobility. Anticonvulsants do not influence the course of epilepsy, but just suppress seizures. Preterm infants are at higher risk for epilepsy, likely due to the etiologies affecting this age group. With neonatal status epilepticus, there is poor outcome, especially noted in preterm compared with full-term infants.

What causes this disease and how frequent is it?

The incidence of neonatal seizures varies depending on location and availability of perinatal care. A study in Kenya from 2010 showed a rate of 142/1572 or 9% of all neonatal admissions with an incidence of 39.5/1000 live births. A study from California found the incidence of neonatal seizures at .95/1000 live births. In India, the incidence was found to be 1.17% with a 11.7/1000 live birth ratio. There are no seasonal variations noted with neonatal seizures.

Etiologies causing neonatal seizures are described in earlier sections. Genetic counseling will be discussed further in other sections.

How do these pathogens/genes/exposures cause the disease?

Seizures arise from excess excitatory activity among neurons that becomes synchronized. Neonates are more susceptible to seizures, likely because compared with adults the balance of excitation and inhibition in neonatal brain favors excitation. GABA in neonatal brain is not inhibitory; it is excitatory. Therefore, seizures are more frequent in neonates and propagate more quickly than in adults.

With trauma, hypoxic ischemic insult and strokes, the balance of inhibition and excitation is disrupted across the neuronal membrane. Seizures are even more likely in an already more excitatory environment of the neonate. The neuronal plasticity of neonatal brain means that seizures in this age group may alter how neural pathways develop more than in adult brain. Long-term sequelae may be as much or more due more to alteration of neural pathways than to destruction of neurons.

Other clinical manifestations that might help with diagnosis and management

The timing of the seizure onset can help to determine what is the more likely cause of the seizure. If the seizure first occurs within the first 24 hours after birth, it is more likely related to prenatal environment or to delivery. Possible causes are maternal drugs, sepsis/meningitis, hypoxic ischemic encephalopathy and subarachnoid hemorrhage/birth trauma.

If the seizure occurs at 24-72 hours of age, likely causes are stroke, intraventricular hemorrhage or other intracranial hemorrhage, cortical malformation, meningitis/sepsis, drug withdrawal, neurocutaneous syndromes (tuberous sclerosis, incontentia pigmenti), hypocalcemia, hypoglycemia, and metabolic disorders (urea cycle, pyridoxine dependency or glycine encephalopathy).

If seizures occur later in the first week, metabolic causes such as methylmalonic academia, urea cycle abnormalities, mitochondrial disorders or proprionic academia are more likely. In addition, 5th day fits or familial neonatal seizures, stroke/venous thrombosis, kernicterus, and tuberous sclerosis may be causes. After the first week, seizures are likely related to cortical dysplasia, viral encephalitis, tuberous sclerosis and metabolic disorders.

What complications might you expect from the disease or treatment of the disease?

Complications from prolonged or frequent neonatal seizures include global developmental delay, cerebral palsy/spasticity with possible contractures, epilepsy later in life, feeding issues or swallowing issues. Again, this is usually related to the underlying etiology causing the seizures. Treatment complications may include osteopenia, lethargy and possible cognitive issues depending on the anticonvulsant used. Prognosis is covered in another section.

Are additional laboratory studies available; even some that are not widely available?

If a patient is considered to have partial seizures that are intractable to medication treatment, that neonate may be considered an epilepsy surgery candidate. Furthermore, work-ups for these patients are performed to verify that they are having seizures arising from one location. The evaluations include functional neuroimaging studies such as PET and ictal SPECT scans which will confirm the epileptogenic zone noted on EEG. Often times, epilepsy surgery is only considered in catastrophic seizures such as hemimegalencephaly where refractory status epilepticus often happens and the prognosis for seizure control is poor. There are genetic markers available commercially as well and this is discussed below. The advent of various gene panels such as Gene Dx has improved the yield for genetic testing in many epilepsy patients, including neonates, and may be helpful in determining genetic etiologies in these children. In addition, there is more prevalence of whole exome sequencing and other genetic tests, which may help to determine what genetic disorders underlie neonatal seizure conditions.

How can neonatal seizures be prevented?

Prevention depends on the etiology. Avoidance of sepsis and metabolic derangements, improvements in delivery methods and oxygenation have helped to reduce neonatal seizures. Early diagnosis, detection and treatment of seizures and subclinical seizures have decreased long-term sequelae. If neonatal seizures are related to inborn errors of metabolism, specific diets may help prevent seizures.

Genetic counseling for neonates with disorders such as benign familial neonatal seizures, pyridoxine deficiency/dependent seizures and metabolic disorders with a known mutation can help some couples avoid these disorders in future pregnancies. Benign familial neonatal seizures are inherited with an autosomal dominant pattern. Genetic markers are commercially available (e.g., KCNQ2 or KCNQ3).

Most of these types of etiologies have a benign prognosis. Other genetic illnesses such as inborn error of metabolism have a poor prognosis. Availability of genetic testing varies depending on the disease. Pyridoxine deficiency has a commercially available marker (ALDJ7A1) in serum. Pyridoxine deficiency is autosomal recessive; there is a 25% chance of the condition in a sibling, and 50% will be an asymptomatic carrier.

What is the evidence?

As stated before in prior sections, there are no randomized controlled medication trials for efficacy or side effect of treatment options in neonatal seizures and there are few studies concerning neonatal seizures and diagnostic tests or etiology. Therefore, most of the bibliography listed below are review articles, case series, or low sample sizes. This points to the lack of research studies currently available.

Glass, HC, Sullivan, JE. "Neonatal seizures". Curr Treat Options Neurol. vol. 11. 2009. pp. 405-13.

Plouin, P, Kaminska, A. "Neonatal seizures". Handb Clin Neurol. vol. 111. 2013. pp. 467-76.

(Good general overview of neonatal seizures.)

Cross, JH. "Differential diagnosis of epileptic seizures in infancy including the neonatal period". Semin Fetal Neonatal Med. vol. 18. 2013. pp. 192-5.

(Good review of differential diagnosis for neonatal seizures.)

Loman, AM, ter Horst, JH, Lambrechtsen, FA, Lunsing, RJ. "Neonatal seizures: aetiology by means of a standardized work-up". Eur J Paediatr Neurol. vol. 18. 2014. pp. 360-7.

(Evaluation process involved for neonatal seizures.)

Osmond, E, Biletop, A, Jary, S, Likeman, M, Thoresen, M, Luyt, K. "Neonatal seizures: magnetic resonance imaging adds value in the diagnosis and prediction of neurodisability". Acta Paediatr. vol. 103. 2014. pp. 820-6.

(Use of MRI as preferred evaluation with neonatal seizures.)

Gospe, SM, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K. "Gene Reviews (internet)". University of Washington. 1993-2010 Dec 07.

(For general information on pyridoxine dependent seizures.)

Bellini, G, Miceli, F, Soldovieri, MV, Miraglia del Giudice, E, Pascotto, A, Talialatela, M, Pagon, RA, Bird, TD, Dolan, CR, Stephens, K. Gene Reviews (internet). University of Washington. 1993-2010 Apr 27.

(For general information on benign familial neonatal seizures.)

Glass, HC, Wirrell, E. "Controversies in neonatal seizure management". J Child Neurol. vol. 24. 2009. pp. 591-9.

(Provides a good review in the controversies in management of neonatal seizures.)

Lawrence, R, Inder, T. "Neonatal status epilepticus". Semin Pediatr Neurol. vol. 17. 2010. pp. 163-8.

(A good review of status epilepticus.)

Glass, HC, Wusthoff, CJ, Shellhaas, RA, Tsuchida, TN, Bonifacio, SL, Cordeiro, M, Sullivan, J, Abend, NS, Chang, T. "Risk factors for EEG seizures in neonates treated with hypothermia: a multicenter cohort study". Neurology. vol. 82. 2014. pp. 1239-44.

(An article discussing use of EEG with patients who undergo hypothermia.)

Clancy, RR. "Prolonged electroencephalogram monitoring for seizures and their treatment". Clin Perinatol. vol. 33. 2006. pp. 649-65.

(This is also a good review on neonatal EEG.)

McCoy, B, Hanh, CD. "Continuous EEG monitoring in the neonatal intensive care unit". J Clin Neurophysiol. vol. 30. 2013. pp. 106-14.

Glass, HC. "Neonatal seizures: advances in mechanisms and management". Clin Perinatol. vol. 41. 2014. pp. 177-90.

(Two articles on general discussion on continuous EEG and amplitude integrated EEG.)

Clancy, RR. "The newborn drug development initiative workshop: Summary proceedings from the neurology group on neonatal seizures". Clin Ther. vol. 28. 2006. pp. 1342-52.

Hellstrom-Westas, L, Boylan, G, Agren, J. "Systematic review of neonatal seizure management strategies provide guidance on antiepileptic treatment". Acta Paediatr. vol. 104. 2015. pp. 123-9.

Donovan, MD, Griffin, BT, Kharoshankaya, L, Cryan, JF, Boyan, GB. "Pharmacotherapy for neonatal seizures: current knowledge and future perspectives". Drugs. vol. 76. 2016. pp. 647-61.

(Three treatment review articles.)

Holmes, GL. "The long-term effects of neonatal seizures". Clin Perinatol. vol. 36. 2009. pp. 901-14.

(This is a review article on the basic pathophysiology of neonatal seizures.)

Ongoing controversies regarding etiology, diagnosis, treatment

There are continuing controversies as to the acute treatment options and long term management of neonatal seizures. There are no double blinded studies concerning medication efficacy and side effects. This is due to the ethical dilemma of treating neonates with untested medications and the potential long term side effects of medication.

With the advent of hypothermia as a treatment for hypoxic ischemic encephalopathies (HIE) , there are concerns in terms of detecting seizures in this specific population of the neonatal ICU and in looking at preventative use of anticonvulsants. One study performed in 2014 demonstrated frequent electrographical seizures seen in the first day of therapeutic hypothermia with a rebound noted on the fourth day of therapy. There is a recent article suggesting that there is lower seizure frequency in children who have mild HIE and undergo therapeutic hypothermia, but no improvement in seizure frequency with therapeutic hypothermia with severe HIE.

In basic science literature, there have been some studies on rats looking into neuroprotective aspects of topiramate and levetiracetam but no randomized multicenter trials on these medications clinically in neonates. In addition, long term management for neonatal seizures in an outpatient setting has been controversial as to the length of treatment and when to wean medications off.

Finally, the need for continuous EEG in the detection of subclinical seizures has been debated; this includes whether subclinical seizures are dangerous and cause brain damage and whether aggressive treatment is warranted. Many studies have also debated as to the usefulness of amplitude integrated EEG and how this compares to the standard neonatal EEG.

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