Original Article Journal of Child Neurology 1-8 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814549243 jcn.sagepub.com
Sudden Infant Death Syndrome, Sleep, and Seizures Toke Hoppenbrouwers, PhD1
Abstract Working hypothesis: benign febrile seizures seen in 7% of infants before 6 months play a role in the terminal pathway in a subset of sudden infant death syndrome victims. Supporting evidence: (1) lack of 5-hydroxitryptamine, one consistent finding in sudden infant death syndrome that Kinney et al coined a developmental serotonopathy, is consistent with risk for seizures. (2) Non–rapid eye movement sleep increasing during the age of highest risk for sudden infant death syndrome facilitates some seizures (seizure gate). (3) Sudden unexpected death in epilepsy is associated with severe hypoxemia and hypercapnia during postictal generalized electroencephalographic (EEG) suppression. In toddlers, sudden unexplained deaths are associated with hippocampal abnormalities and some seizures. (4) The sudden nature of both deaths warrants an exploration of similarities in the terminal pathway. Moreover, sudden infant death syndrome, febrile seizures, sudden unexplained death in childhood, and sudden unexpected death in epilepsy share some of the following risk factors: prone sleeping, infections, hyperthermia, preterm birth, male gender, maternal smoking, and mutations in genes that regulate sodium channels. State-of-the-art molecular studies can be exploited to test this hypothesis. Keywords sudden infant death syndrome, sleep, seizures Received February 11, 2014. Received revised July 28, 2014. Accepted for publication August 02, 2014.
The rate of sudden infant death syndrome has declined because of the Back-to-Sleep campaign and changes in other environmental risk factors. Sudden infant death syndrome, however, has not been eradicated. Death seems to be silent and its relationship with sleep, in particular sleep time, is undisputed and may account for the fact that death has virtually never been witnessed.1 Both modifiable and immutable risk factors have been established as well as a deficit in the brainstem serotonin system of sudden infant death syndrome victims, a condition that Kinney et al2 have called a developmental serotonopathy. The stealth mechanism of death in a relatively small number of infants has made the search for etiology extremely challenging. This communication proposes a working hypothesis about the terminal pathway in a subset of sudden infant death syndrome that suggest a role for febrile seizures in sudden death. It is based on a broad review of the neuroscience and clinical literature and capitalizes on both recent advances in molecular biology and some provocative pathologic studies in age groups beyond the sudden infant death syndrome range.3-5 In the past, a role for seizures in sudden infant death syndrome has been summarily dismissed because of the belief among pediatric clinicians that simple febrile seizures are benign.6 Direct evidence either for or against this working hypothesis is lacking. In 25% of cases of febrile seizures, a family history has been documented. This finding led Vestergaard et al7 to postulate that siblings of infants with febrile seizures should have a higher risk for sudden infant death syndrome than siblings of children who
had never experienced one. They found a sudden infant death syndrome incidence of 1.53 and 1.70 per 1000 live births, respectively, numbers that failed to support a shared ‘‘susceptibility’’ hypothesis. Although the belief in benign febrile seizures is valid, once these are terminated, especially if they occurred during sleep, they leave no footprint. In the postulated rare instance that death ensues, it could not possibly be attributed to febrile seizures, reinforcing the belief that simple febrile seizures are benign. By stressing the tentative nature of this hypothesis, and avoiding unnecessary worry for parents of babies with febrile seizures, a re-evaluation of the almost axiomatic belief that single febrile seizures are benign, is urged. Two issues deserve recognition: 1.
The age paradox
In 1993, the International League Against Epilepsy defined a febrile seizure as ‘‘occurring in childhood after age 1 month, associated with febrile illness.’’8 1
Division of Neonatal Medicine, University of Southern California, Los Angeles, CA, USA
Corresponding Author: Toke Hoppenbrouwers, PhD, University of Southern California, Division of Neonatal Medicine, 4650 Sunset Blvd, Los Angeles, CA 90027, USA. Email: [email protected]
2
Journal of Child Neurology
The definition issued in 1999 by the American Academy of Pediatrics9 states, ‘‘A simple febrile seizure is a brief generalized seizure (
Sudden Infant Death Syndrome, Sleep, and Seizures Toke Hoppenbrouwers, PhD1
Abstract Working hypothesis: benign febrile seizures seen in 7% of infants before 6 months play a role in the terminal pathway in a subset of sudden infant death syndrome victims. Supporting evidence: (1) lack of 5-hydroxitryptamine, one consistent finding in sudden infant death syndrome that Kinney et al coined a developmental serotonopathy, is consistent with risk for seizures. (2) Non–rapid eye movement sleep increasing during the age of highest risk for sudden infant death syndrome facilitates some seizures (seizure gate). (3) Sudden unexpected death in epilepsy is associated with severe hypoxemia and hypercapnia during postictal generalized electroencephalographic (EEG) suppression. In toddlers, sudden unexplained deaths are associated with hippocampal abnormalities and some seizures. (4) The sudden nature of both deaths warrants an exploration of similarities in the terminal pathway. Moreover, sudden infant death syndrome, febrile seizures, sudden unexplained death in childhood, and sudden unexpected death in epilepsy share some of the following risk factors: prone sleeping, infections, hyperthermia, preterm birth, male gender, maternal smoking, and mutations in genes that regulate sodium channels. State-of-the-art molecular studies can be exploited to test this hypothesis. Keywords sudden infant death syndrome, sleep, seizures Received February 11, 2014. Received revised July 28, 2014. Accepted for publication August 02, 2014.
The rate of sudden infant death syndrome has declined because of the Back-to-Sleep campaign and changes in other environmental risk factors. Sudden infant death syndrome, however, has not been eradicated. Death seems to be silent and its relationship with sleep, in particular sleep time, is undisputed and may account for the fact that death has virtually never been witnessed.1 Both modifiable and immutable risk factors have been established as well as a deficit in the brainstem serotonin system of sudden infant death syndrome victims, a condition that Kinney et al2 have called a developmental serotonopathy. The stealth mechanism of death in a relatively small number of infants has made the search for etiology extremely challenging. This communication proposes a working hypothesis about the terminal pathway in a subset of sudden infant death syndrome that suggest a role for febrile seizures in sudden death. It is based on a broad review of the neuroscience and clinical literature and capitalizes on both recent advances in molecular biology and some provocative pathologic studies in age groups beyond the sudden infant death syndrome range.3-5 In the past, a role for seizures in sudden infant death syndrome has been summarily dismissed because of the belief among pediatric clinicians that simple febrile seizures are benign.6 Direct evidence either for or against this working hypothesis is lacking. In 25% of cases of febrile seizures, a family history has been documented. This finding led Vestergaard et al7 to postulate that siblings of infants with febrile seizures should have a higher risk for sudden infant death syndrome than siblings of children who
had never experienced one. They found a sudden infant death syndrome incidence of 1.53 and 1.70 per 1000 live births, respectively, numbers that failed to support a shared ‘‘susceptibility’’ hypothesis. Although the belief in benign febrile seizures is valid, once these are terminated, especially if they occurred during sleep, they leave no footprint. In the postulated rare instance that death ensues, it could not possibly be attributed to febrile seizures, reinforcing the belief that simple febrile seizures are benign. By stressing the tentative nature of this hypothesis, and avoiding unnecessary worry for parents of babies with febrile seizures, a re-evaluation of the almost axiomatic belief that single febrile seizures are benign, is urged. Two issues deserve recognition: 1.
The age paradox
In 1993, the International League Against Epilepsy defined a febrile seizure as ‘‘occurring in childhood after age 1 month, associated with febrile illness.’’8 1
Division of Neonatal Medicine, University of Southern California, Los Angeles, CA, USA
Corresponding Author: Toke Hoppenbrouwers, PhD, University of Southern California, Division of Neonatal Medicine, 4650 Sunset Blvd, Los Angeles, CA 90027, USA. Email: [email protected]
2
Journal of Child Neurology
The definition issued in 1999 by the American Academy of Pediatrics9 states, ‘‘A simple febrile seizure is a brief generalized seizure (
