Benign Neonatal Convulsions
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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 neurologic 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 brief seizures are followed by a short or no postictal state. The episodes usually resolve within days but may continue for several months and have no neurologic sequelae.
The occurrence of status epilepticus is common in benign idiopathic neonatal convulsions (BINC) but is uncommon in benign familial neonatal convulsions (BFNC). Because the condition benign idiopathic neonatal convulsions 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. [1, 2, 3, 4]
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. [3, 5] Definite advantages exist in approaching the subject from each position. Too broad a definition in a research situation can lead to confusion when searching for a common pathology. Too narrow a definition in the clinical setting may result in confusion about a clinical diagnosis. Later, when the mechanisms are better 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. See Juvenile Myoclonic Epilepsy, Myoclonic Epilepsy Beginning in Infancy or Early Childhood, Partial Epilepsies, and Complex Partial Seizures for more information on these topics.
For more information, see the following:
The genetics of benign familial neonatal convulsions (BFNC) is currently an area of active investigation; inheritance of this condition is autosomal dominant. [6]
Loci on chromosome arm 20q have been identified for most families, and 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. [7, 8, 9, 10, 11, 12, 13, 14] Both mutations encode voltage-gated potassium channel subunits. [15] The specific location of the mutation appears to vary from family to family and at least 1 family has been noted to include an increased incidence of rolandic epilepsy. [16]
Several additional genes have been associated with benign familial neonatal convulsions in single families, including KCNQ5 M-type potassium channel in one family. [17] 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. [18, 19]
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 (CNS). [20, 21]
Given the severity of the impairment to the M-type potassium channel, that these seizures are difficult to treat is not surprising, because 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 upregulating 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. [22, 23, 24]
A KCNQ2 mutation was identified in a family with seizure onset between 2-4 months of age, which may fulfill the diagnosis of BFNIS (benign familial neonatal-infantile seizures). Genomic deletion of KCNQ2 causes neonatal onset, whereas a point mutation in KCNQ2 causes delayed-onset epilepsy. This indicates the role of KCNQ2 beyond a typical neonatal period. A small portion of affected patients suffer afebrile seizures later in their childhood or adulthood. A new mutation is responsible for the malignant form up to and including epileptic encephalopathy. [25]
A number of cases have been reported in which benign idiopathic or familial neonatal convulsions 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. [26, 27, 28, 29]
A complicating factor is that in neonates the action of the gamma-aminobutyric acid (GABA)–A receptor is excitatory rather than inhibitory in the brain. [30, 31, 32, 33]
GABA is initially excitatory as a result of a high intracellular concentration of chloride ([Cl–]). Then, GABA-releasing and glutamatergic synapses are formed sequentially. There is a primitive network-driven pattern of electrical activity in all developing circuits: the giant depolarizing potentials (GDPs), which are generated in part by the excitatory actions of GABA. This pattern allows the generation of large oscillations of intracellular calcium, even in neurons that have few synapses and an activity-dependent modulation of neuronal growth and synapse formation. Later on, once a sufficient density of glutamate and GABA synapses has been generated and inhibition becomes necessary, a chloride-excluding system becomes operative, an event that is activity dependent. As a result, chloride is efficiently pumped from the intracellular milieu, GABA begins to exert its conventional inhibitory action, and the primitive pattern is replaced by more diverse and elaborate patterns of activity. [34]
The pathophysiology of benign idiopathic neonatal convulsions (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. [30, 31, 32, 33]
Ion channels regulate the flow of ions into and out of the cell and are absolutely critical for a wide range of biological processes, including the transmission of signals in the nervous system. Disrupting ion channel function can have disastrous consequences. [35]
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. [36] 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 are likely also 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. [37, 38, 39] These sorts of multifactorial etiologies are more difficult to define precisely. More research is needed in this area, and apparent monogenic diseases, such as benign familial neonatal convulsions, provide important insight into more complex etiologies.
Several causes have been proposed for benign idiopathic neonatal convulsions (BINCs), including rotavirus infection, low central nervous system (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. [3]
Most families in which benign familial neonatal convulsions occurs have abnormalities in the genes coding for the KCNQ2 and KCNQ3 potassium channels. [40, 41] The gene for this disorder has been localized to 2 chromosomes in many, but not all, of the families: BFNC 1, locus on band 20q13.3 (voltage-gated potassium channel gene, KCNQ2) and BFNC 2, band 8q24 (potassium channel gene, KCNQ 3). [42]
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 upregulated to accommodate for the deficiency in function of the abnormal channels.
Clearly, the immature infant brain is different electrophysiologically during early development. Gamma-aminobutyric acid (GABA) has a seemingly paradoxical excitatory effect. [30] Glutamate synapses are slow to develop, and there is delayed expression of the K+/Cl– cotransporter KCC2 and NKCC1. [31] 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 excitatory postsynaptic responses (EPSPs) and inhibitory postsynaptic potentials (IPSPs) gradually approach the adult state. Because 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.
Benign neonatal convulsions in the United States and internationally are uncommon; that is, 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 reports from Japan and China exist. [43, 44, 6] This is certainly an artifact of observation rather than occurrence. Part of the reason for this is likely the stability of reporting resources in European countries.
In benign idiopathic neonatal convulsions (BINCs), males are affected somewhat more frequently than females (62%) in examined cases, [36] whereas in benign familial neonatal convulsions (BFNCs), the frequency in males is equal to that in females, compatible with simple autosomal dominant inheritance. [36] 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.
There is also a slight age difference between the 2 conditions. In benign idiopathic neonatal convulsions, 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. [45]
Patients may be slightly older at onset in benign familial neonatal convulsions, with some patients in previously identified families several weeks old. Characteristically, the onset of benign familial neonatal convulsions occurs when neonates are aged 2 days. [1, 2, 4]
Interestingly, unaffected family members of patients with benign familial neonatal convulsions have a higher-than-expected risk of developing epilepsy in later life. Presently, family studies have not clarified whether these relatives always share the genetic defect in the potassium channel. [3, 36]
The risk of seizures later in life is 11-16% in benign familial neonatal convulsions (BFNCs) and somewhat less in benign idiopathic neonatal convulsions (BINCs), perhaps as low as 2%. Other reported problems have been sporadic and within the incidence range expected for the general population. [36]
Overall, as the name implies, benign neonatal convulsions have an excellent prognosis and resolve without neurologic sequelae.
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 neurologic problems is the same as expected in the general population.
For patient education information, see the Brain and Nervous System Center, as well as Seizures in Children.
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Nitin C Patel, MD, MPH, FAAN Professor of Clinical Pediatrics and Neurology, Southern Illinois University School of Medicine; Private Practice, Columbia Center for Child Neurology
Nitin C Patel, MD, MPH, FAAN is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Headache Society, Child Neurology Society
Disclosure: Nothing to disclose.
Nancy Theresa Rodgers-Neame, MD Assistant Professor, Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine; Director, Florida Comprehensive Epilepsy and Seizure Disorders Program
Nancy Theresa Rodgers-Neame, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Womens Association, Society for Neuroscience, Southern Medical Association
Disclosure: Nothing to disclose.
Robin D Riggins, RN, MSN, CPNP Pediatric Nurse Practitioner, Department of Pediatric Neurology, University of Missouri Health Care Hospitals and Clinics
Robin D Riggins, RN, MSN, CPNP is a member of the following medical societies: National Association of Pediatric Nurse Practitioners, American Association of Neuroscience Nurses
Disclosure: Nothing to disclose.
Harsha N Patel, MD, MPH Assistant Professor, Department of Child Health, University Hospital; Assistant Professor, Department of Pediatrics, University of Missouri-Columbia School of Medicine
Disclosure: Nothing to disclose.
Amy Kao, MD Attending Neurologist, Children’s National Medical Center
Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society
Disclosure: Have stock (managed by a financial services company) in healthcare companies including AbbVie, Allergan, Celgene, Cellectar Biosciences, Danaher Corp, Mckesson.
Robert J Baumann, MD Professor of Neurology and Pediatrics, Department of Neurology, University of Kentucky College of Medicine
Robert J Baumann, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, and Child Neurology Society
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Reference Salary Employment
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