AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Benign neonatal convulsions are defined as seizures with onset after birth through day 28 in an otherwise healthy child with no other known medical or neurological problems. Such cases may be familial or isolated. Psychomotor development should be normal for a full-term or near full-term infant with benign convulsions. Between seizures, findings on neurologic examination should be normal. Clinically, the seizures are frequent and brief, occasionally occurring many times within a day. The episodes usually resolve within days but may continue for several months and have no neurological sequelae. The occurrence of status epilepticus is common in benign idiopathic neonatal convulsions (BINC) but is uncommon in benign familial neonatal convulsions (BFNC). Because BINC is a diagnosis of exclusion, it is nearly always made in retrospect, when the seizures spontaneously resolve and the infant is found to have neurologically normal development.

At the outset, considering how broadly to define benign neonatal convulsions is important: for example, whether to include those with myoclonic or partial onset components or those with a known or treatable etiology. Certainly, multiple presentations of seizures that may have a benign long-term outcome are possible in the neonatal period. Definite advantages exist in approaching the subject from each position. Too broad of a definition in a research situation can lead to confusion when searching for a common pathology. Later, when the mechanisms are more well defined, broader groups not meeting the initial criteria may exist.

Clinically, the more important considerations are taking an appropriate approach to the patient and family, making the correct diagnosis, and pursuing treatment options concordant with the situation. Sometimes, the correct clinical plan may include a decision not to treat a benign condition with medications that often are not so benign. It should also be emphasized that a definitive diagnosis may take some time, given the often retrospective nature of the diagnosis.

For the purposes of this article, myoclonic and partial onset seizures of the neonatal period are considered separate entities. They are mentioned briefly during the discussion on differential diagnosis.

Pathophysiology

The genetics of BFNC is currently an area of active investigation. Inheritance is autosomal dominant. Loci on chromosome arm 20q have been identified for most families. At least one family was identified to have a locus on chromosome arm 8q. Some of these loci have been identified further as specific mutations in the KCNQ2 and KCNQ3 M-type potassium channel proteins. The specific location of the mutation appears to vary from family to family.

Several additional genes have been associated with BFNC in single families, including KCNQ5 M-type potassium channel in one family. Another family has been noted to have abnormalities in the acetylcholine alpha-4 receptor subunit, which also has been associated with autosomal dominant nocturnal frontal lobe epilepsy.

Expression of the mutated genes in xenopus oocytes has provided some insight into how the potassium channel mutation leads to lowering of the seizure threshold. The potassium current was reduced in the channel expressed by the mutated gene to 5% of that in the channel expressed by the normal gene. However, voltage sensitivity and kinetics were not affected. The effect is therefore to impair repolarization of the neuronal cell membrane, leading to hyperexcitability of the central nervous system.

Given the severity of the impairment to the M-type potassium channel, that these seizures are difficult to treat is not surprising, since no currently used antiepileptic medications are known to increase the efficiency of the potassium channel. What is surprising is the self-remitting nature of the condition, that many individuals never have another seizure, and that the profound abnormalities of the voltage-gated potassium channel do not appear to compromise the nervous system in any other way. Possibly, some intrinsic method exists for up-regulating expression of the normal potassium channel genes, or the neurons may find other ways of normalizing the hyperexcitability, but these theories remain to be demonstrated.

A number of cases have been reported where BINC or BFNC have preceded the development of epilepsy later in life. Similarly, perhaps, febrile seizures early in life may predispose to later development of epilepsy. Given the polygenic etiology of susceptibility to epilepsy, it is not surprising that an abnormality in part of the system maintaining homeostasis within the neuron should render the neuron more prone to dysfunction.

The pathophysiology of BINC has been less well defined and remains somewhat elusive. One issue is that the neonatal brain is more prone to seizures, which has been demonstrated in a number of experimental systems. Several etiologies have been proposed as a result of isolated findings of lowered zinc level in the cerebrospinal fluid and low levels of vitamin B-6. Both of these compounds are important cofactors in ligand-gated ion channel function. However, these findings have not been robust, and the search continues. These seizures likely also are linked in some way to ion channel dysfunction as is found in the familial seizures, but they may be caused by multiple etiologies or occur as a multigenomic entity. These sorts of multifactorial etiologies are more difficult to define precisely. More research is needed in this area, and apparent monogenic diseases, such as BFNC, provide important insight into more complex etiologies.

Frequency

United States

Benign neonatal convulsions in the United States are uncommon, ie, not rare but not common, either. Underreporting is likely an issue. Seizures that resolve in the early months of life without sequelae and normal neonatal development are often lost to follow up. Exact frequencies are undetermined. Families identified with the familial form thus far have been primarily of western European origin, although one report from Japan exists. Part of the reason for this is likely the stability of reporting resources in European countries.

International

Benign neonatal convulsions also are uncommon internationally. Families identified with the familial form thus far have been primarily of western European or Japanese origin. This is certainly an artifact of observation rather than occurrence.

Mortality/Morbidity

The risk of seizures later in life is 11-16% in BFNC and somewhat less in BINC, perhaps as low as 2%. Other reported problems have been sporadic and within the incidence range expected for the general population

Race

All cases to date have been reported in families of European origin.

Sex

In BFNC, the frequency in males is equal to that in females, compatible with simple autosomal dominant inheritance.

In BINC, males are affected somewhat more frequently than females (62%) in examined cases (N=199). With such a small number of cases reported, this may be due to reporting bias or simple sampling error, or it may represent a real difference in frequency.

Age

• In BINC, patients are aged 1-7 days at onset, with day 5 the most frequently reported day of onset. The frequent onset on the fifth day of life is responsible for the term "fifth day disease" or "fifth day fits," which continues to be used in the pediatric literature. However, in actuality, fifth day fits are most likely seizures that were reportedly linked to the use of hexachlorophene (pHisoHex), which now has been discontinued.
• Patients may be slightly older at onset in BFNC, with some patients in previously identified families several weeks old. Characteristically, the onset of BFNC occurs when neonates are aged 2 days.
• Interestingly, "unaffected" family members of patients with BFNC have a higher-than-expected risk of developing generalized epilepsy in later life. Presently, family studies have not clarified whether these relatives always share the genetic defect in the potassium channel; they probably do.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The history should be free of suspicion of causative elements for neonatal seizures.
• • Such elements include prenatal or perinatal stroke, perinatal asphyxia, fever, persistent lethargy, pertinent maternal illness or drug abuse, signs of metabolic dysfunction, or neurological abnormalities.
  • Other criteria that have been noted but may be of limited value are a lack of neurological or genetic abnormalities in siblings or other family members or metabolic dysfunction of any cause. A 5-minute Apgar score less than 9 also has been suggested but is almost certainly too stringent to require for diagnosis.
• Diagnostic criteria have been suggested by Miles and Holmes as well as Plouin for both BFNC and BINC.
• • Diagnostic criteria - Benign idiopathic neonatal convulsions
    • Infants born after 39 weeks' gestation
    • Apgar score of 9 or more at 5 minutes (lower scores should not exclude the diagnosis if other criteria are met)
    • Presence of a seizure-free interval between birth and the onset of seizures
    • Clonic and/or apneic seizures
    • Negative findings on evaluation for alternative etiology
    • Normal developmental and intellectual outcome (largely determined in retrospect)
    • Lack of seizures beyond the neonatal period
  • Diagnostic criteria - Benign familial neonatal convulsions
    • Normal neurologic examination findings
    • Negative findings on evaluation for alternative etiology
    • Normal developmental and intellectual outcome (retrospective criteria)
    • Positive family history of newborn or infantile seizures
    • Onset of seizures during neonatal period or early infancy

Physical

Physical and neurologic examination findings should be normal during the interictal period.

Causes

• Several causes have been proposed for BINC, including rotavirus infection, low CNS zinc levels, and vitamin B-12 deficiency. None of these causes has been confirmed. The more likely explanation is the presence of a self-limited malfunction in one of the ligand-gated or voltage-gated ion channels.
• Most families in which BFNC occurs have abnormalities in the genes coding for the KCNQ2 and KCNQ3 potassium channels.
• • This defect leads to abnormal repolarization of the neuronal membrane and likely causes the neonatal seizures.
  • The real puzzle is why this profound abnormality in membrane polarization does not lead to more problems in later life or persistent seizures extending from the neonatal period. This may be evidence that the drive toward homeostasis in the brain is strong, with redundant systems capable of maintaining a seizure-free state until more than one system is affected, or that systems are affected that do not have the redundancy of the voltage-gated potassium channels. Moreover, the normal potassium channels may be up-regulated to accommodate for the deficiency in function of the abnormal channels.
  • Clearly, the immature infant brain is different electrophysiologically during early development. GABA has a seemingly paradoxical excitatory effect. Glutamate synapses are slow to develop, and there is delayed expression of the K⁺/Cl^- cotransporter KCC2. The primary inhibition in the neonatal brain is presynaptic rather than postsynaptic. As the brain matures and expression of postsynaptic inhibitory and excitatory processes develop, the maintenance of neuronal homeostasis as well as postsynaptic EPSPs and IPSPs gradually approach the adult state. Since all of these processes are under development at the same time as neonatal convulsions appear, it is likely that neonatal seizures are affected by the normal developmental sequence of the other neurotransmitter systems.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Vitamin B-6 deficiency
Maternal drug abuse

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The reason for ordering tests in BFNC and BINC is to exclude the presence of any etiology for the seizures. The diagnosis of benign infantile convulsions of either type requires that no other explanation exist for the seizures. Order tests for individual patients with a plan for that patient in mind. While a "shotgun" approach is wasteful and unreasonable, it is also important not to miss a diagnosis of a treatable meningoencephalitis in the early stages or intracranial hemorrhage. Both of these conditions in neonates lack the typical findings observed in older infants and children, and the only early symptom may be seizures. Also entertain a healthy suspicion for child abuse in neonates, who often have just arrived home from the hospital following delivery. Review of basic screening laboratory studies performed at delivery may also be helpful.
• • Chemistries - Basic metabolic panel plus calcium, magnesium, phosphorus, thyroid function tests, and possibly B vitamin levels
  • Basic hematologic labs - CBC, prothrombin time, activated partial thromboplastin time
  • Lumbar puncture - Cerebrospinal fluid examination to exclude neonatal meningoencephalitis or occult blood
• Any abnormalities found that are inconsistent with a diagnosis of benign neonatal convulsions require the appropriate further workup and treatment.

Imaging Studies

• MRI or CT scan of the brain
• • Perform one or both of these tests in every patient with neonatal seizures to exclude structural lesions and intracranial hemorrhage.
  • An argument can be made that both are needed since CT scan yields better information on acute hemorrhage and skull fracture, and MRI shows better brain structural detail.

Other Tests

• Electroencephalography
• • The classic EEG observed in 60% of patients with BINC is a rolandic discharge in the theta range that is alternating or discontinuous with intermixed sharp activity. Interhemispheric asymmetry is observed frequently; it is unresponsive to stimulation of any kind. This pattern often is termed theta pointu altérnant.
  • The remaining patients with BINC have either a normal interictal EEG or focal abnormalities. The EEG during seizures is most often high-voltage (200-400 µV) generalized discharges, which may appear to have a focal onset.
  • In BFNC, the interictal EEG is most commonly normal (50-70% of patients). The theta pointu altérnant pattern also is observed but only in approximately 25% of patients. In a small percentage of patients, focal, often rolandic, discharges or spikes may be present.
  • In selected patients, continuous video-EEG can be used to confirm behavioral events concordant with abnormal EEG and to confirm that treatment is effective. The state of the patient and improvement or deterioration can make decision-making easier and facilitate accurate communication with an often anxious family.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Although the seizures are benign, general agreement exists that they should be treated, particularly BINC.

• Treatment with antiepileptic medications may prevent the occurrence or reduce the length of the period of status epilepticus. Continuing antiepileptic treatment for more than 10 days may not be necessary in BINC. One thing that should be kept in mind with treatment is that while seizures may abate the EEG may remain abnormal. In some cases, the EEG may change appearance but remain abnormal nevertheless.
• The medications used most frequently are benzodiazepines, phenobarbital, and fosphenytoin, but no particular reason exists for the preferential use of these drugs rather than some of the newer drugs, except for their current availability in intravenous (IV) formulations and the long-term experience with their use in neonates.
• When IV and liquid formulations become available, some of the newer drugs may prove to be of greater benefit in the future owing to their multiple mechanisms of action and their neuromodulatory/neuroprotective effects.
• The disadvantages of phenobarbital and benzodiazepines are that they are overdosed easily in the neonate and can be very sedating.
• Fosphenytoin may be used acutely, but phenytoin is absorbed unpredictably in the neonate and should not be used as an oral preparation.
• Use caution when treating status epilepticus with phenobarbital in neonates. Mistaking a normal deep anesthesia EEG in this age group with a burst suppression pattern of status epilepticus is easy.
• Do not treat neonates in whom benign convulsions are suspected with valproate because of increased risk of liver failure with the drug and the benign nature of the syndrome.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

No specific antiepileptic medication is preferred for the treatment of benign neonatal convulsions. In general, most epileptologists agree that status epilepticus should be treated when it occurs. Most neonates are best treated at this time with phenobarbital because of long experience with the drug, convenient monitoring, and adequate IV and PO absorption in the neonate. However, treatment has not been shown unequivocally to have an effect except possibly to decrease the duration or severity of the seizures. By definition, the seizures resolve in days (BINC) to weeks (BFNC).

Limit the choice of antiepileptic drug to those with no serious potential adverse effects. Most notably, avoid valproate in this age group if benign convulsions are suspected, since neonates are at the highest risk for liver failure due to valproate. Avoid phenytoin because of cardiac adverse effects, the high possibility of extravasation in neonates, and problems with reliable absorption if administered PO. A trial off the antiepileptic drug(s) should begin soon after the seizures stop and the EEG is normal.

An important factor to remember when treating neonates is that pharmacokinetics and pharmacodynamics are very different than in infants. Do not use infant loading dosages, since they may lead quickly to toxic levels that resolve slowly.

Neonatal pharmacology is complex. Maturation of general liver and renal function is in a period of transition from the fetal to infant state. Stresses or lack of stress on the systems in utero greatly affect the function and maturation of both systems.

Normal glomerular filtration rate (GFR) in the neonate varies in individuals from 1-4 mL/min and can increase rapidly as maturation of the renal cortex progresses. Adult values for GFR are not reached before the infant is aged 2.5-5 months.

Blood flow within the hepatic portal system changes at birth with closing of the ductus venosus. Maturation of the glucuronidation pathway often is slowed. Neonates whose mothers have been exposed to drugs (both prescribed and otherwise) may have active cytochrome P-450 enzymes, and unexposed neonates have initial low activities that increase rapidly with the introduction of drugs such as phenobarbital.

Drug Category: Anticonvulsants

These agents prevent seizure recurrence and terminate clinical and electrical seizure activity.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients should be observed in the inpatient unit until the physician is satisfied that the patient's condition is stabilized and that the infant is feeding well and is free of seizures that compromise feeding or sleeping. In some situations, patients may be seizure free at discharge, but this is not a requirement. Exclude reasonable alternative diagnoses prior to discharge.
• The choice to continue or discontinue any medications started can be tailored to each patient. Consider each of the following:
• • Have the seizures abated to the point that they are no longer interfering with function?
  • What is the family's level of comfort? Fully inform the patient's family of the situation and address their questions and concerns prior to discharge.
  • Is the EEG improved? A normal EEG is not required, but improvement in the EEG indicates that the diagnosis is more likely to be benign and that the prognosis is good for continued improvement at home. Likewise, the typical pattern (ie, theta pointu altérnant) indicates a benign course. Conversely, deterioration of the EEG background or development of a less benign pattern may indicate a less benign prognosis.

Further Outpatient Care

• Follow-up care should consist of one visit soon after discharge to confirm that the patient is physically and neurologically healthy. Perform a repeat EEG at that time.
• Provide later follow-up care spaced at intervals consistent with the physician's and parents' level of comfort. In general, at least 2 serial assessments spaced several months apart should demonstrate a normal EEG, normal developmental milestones, and normal findings on neurologic examination.

In/Out Patient Meds

• No known antiepileptic medications alter the behavior of the potassium channel. Other drugs known to have an effect on potassium transporters are currently being considered for investigation. No studies have revealed any medications that have any advantage over other medications. Select medications on the basis of the following two factors:
• • Appropriateness of the drug in neonates
  • Lack of significant serious adverse effects
• Currently, the most appropriate medication for neonates that can be given in both IV and PO formulation after discharge remains phenobarbital. In the future, other medications may prove more appropriate.
• Specifically, valproate and phenytoin are less appropriate.
• • Generally, valproate in very young patients is reserved for serious conditions that do not respond to therapy with other medications, because the high risk of hepatic complications must be outweighed by the risk of the seizures themselves, a situation that normally is not under consideration in a benign condition.
  • Phenytoin is less appropriate because of unpredictable decreased absorption in the neonate when administered orally.
• The most important consideration in choosing an antiepileptic medication in these patients is to remember that the syndrome is benign. Therefore, any medication chosen should have no risk of serious adverse effects.

Complications

• Patients with BFNC have an increased risk of developing seizures in later life. Depending on the study, 11-20% of patients develop epilepsy in later life. Some families examined also have demonstrated an increased risk of epilepsy in apparently unaffected siblings.

Prognosis

• Overall, as the name implies, benign neonatal convulsions have an excellent prognosis and resolve without neurological sequelae.

Patient Education

• Inform families with the syndrome of the risk of affected siblings, but reassure them as to the benign nature of the syndrome.
• Also alert them to the possible development of epilepsy in later life in affected as well as apparently unaffected children.
• Furthermore, inform them that the incidence of minor neurological problems is the same as expected in the general population.
• For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education article Seizures in Children.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Careful attention to the differential diagnosis of neonatal seizures and appropriate workup avoids most medicolegal problems. However, benign neonatal convulsions are a retrospective diagnosis and frequently present a difficult diagnostic and treatment dilemma even to the most experienced clinicians.
• Keep the family appropriately informed at all stages of the workup, diagnosis, and treatment.

Special Concerns

• Other seizure types often are intermixed in families with inherited seizure disorders. This also is observed in families with benign neonatal convulsions. Children (and apparently unaffected siblings) who have benign neonatal convulsions are at an increased risk of seizures in later life.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Mar 27, 2006