Therapeutic Hypothermia May Be Beneficial for Perinatal Stroke

AUSTIN—Therapeutic hypothermia may be associated with improved outcomes among children with perinatal stroke and encephalopathy, according to research presented at the 2013 Annual Meeting of the Child Neurology Society.

After receiving therapeutic hypothermia, children with perinatal stroke associated with encephalopathy had an improved neuromotor score at age 12 months and a higher cognitive score at age 30 months compared with those who were not treated with hypothermia, reported Mary Jo Harbert, MD.

“People are often surprised to realize that stroke in newborns is as common as stroke in people over age 65,” said Dr. Harbert, Assistant Clinical Professor, Department of Neurosciences, University of California, San Diego. “There is a disparity in neurology that we don’t have acute therapies for perinatal stroke, whereas we have multiple ones for adult stroke. We’re still actually learning more about outcomes for perinatal stroke. It’s clear to us that a newborn with stroke does not have the same clinical presentation or trajectory as an adult with stroke. We do know, however, that kids with perinatal stroke can present with encephalopathy, which can often lead to the diagnosis of global hypoxic ischemic encephalopathy (HIE), and often these kids are treated as such.”

The Case for Therapeutic Hypothermia
Therapeutic hypothermia has been used to treat multiple neurologic disorders in adults, but the most effective use of it in newborns is in those with HIE, said Dr. Harbert. In 2013, a study in the Cochrane Database of Systematic Reviews found that therapeutic hypothermia reduced deaths and improved long-term neurodevelopmental outcomes for term and late preterm newborns with HIE. In 2011, Dr. Harbert and colleagues presented original data from a prospective cohort of 315 neonates with encephalopathy, in which 15 had had a focal ischemic infarct and five were treated with hypothermia. “Although we demonstrated that the kids with stroke who presented with encephalopathy had much poorer long-term cognitive outcomes than their matched counterparts with HIE, there was another interesting finding during the study—70% of the kids with stroke who had not been cooled had neonatal seizures, whereas of the five kids with stroke who had gotten cooled, none of them had neonatal seizures,” said Dr. Harbert.

Cognitive and Neuromotor Improvement After Hypothermia
In 2013, Dr. Harbert’s group sought to determine whether therapeutic hypothermia was associated with improved cognitive, language, and neuromotor outcomes. The children were followed up at ages 12 months and 30 months, at which point they were assessed with use of the Bayley Scales of Infant Development (BSID-II or Bayley-III) and graded with a neuromotor score.

“When you’re looking at cognitive and language outcomes in particular, the primary issue that had to be overcome first was converting the Bayley-III scores to an equivalent of a Bayley-II,” said Dr. Harbert. “This is because of a common clinical observation that the Bayley-III tends to underestimate the prevalence of developmental delay and overestimate developmental abilities.”

The cohort included 332 children with encephalopathy, of whom 15 had a focal ischemic infarct and five received hypothermia. The group who had received hypothermia had similar clinical characteristics to the group who did not receive hypothermia. “They all had approximately the same gestational age, birth weight, modality of delivery, and encephalopathy score,” said Dr. Harbert.

At 12 months of age, the investigators observed no difference in mean Mental Developmental Index scores between the cooled and untreated groups. At 30 months, however, “the cooled group, on average, performed about 31 points higher than the normothermia group, which is a clinically significant difference, about 2 SD,” said Dr. Harbert.

The hypothermia group had a normal neuromotor examination score (median score, 0) at 12 months, compared with the normothermia group, which, on average, had a neuromotor score of 2 on a scale of 0 to 6.

“We also see the same trend at 30 months,” commented Dr. Harbert. “However, this one was not significant, whereas the 12-month finding was. Again, the normothermia group had an average of a little higher neuromotor score, and the hypothermia group not as much. At the 30-month time point, we were a bit hampered by follow-up attrition. Over 90% of our kids were followed up at 12 months, whereas a little over 70% of our kids were followed up at 30 months. And in such a small series it was a little bit more difficult, especially given the fact that one of our kids who had a stroke tragically passed away in an accidental death.”

A More Compelling Question Than Before
Dr. Harbert pointed out several issues that may have affected her group’s findings. “We definitely had some key challenges in this study, and one of them was the lack of available Bayley conversion algorithms for younger ages at the 12-month time point,” she said. “And then we definitely had an issue with sample size. About 5% of kids within an encephalopathy cohort who are presumed to have HIE actually have perinatal stroke, and this was borne out within our study. We also had some follow-up attrition. And then the last challenge for perinatal stroke and HIE is always the variation in the degree of ischemic injury. Not all strokes are created equal. It’s possible that a variation in the degree of injury could have been responsible for this.

“So at the end of the day, it’s still a question of whether cooling is actually associated with improvement in outcomes in perinatal stroke,” she continued. “But given these findings, it’s a more compelling question than before. It also raises the interesting question of, ‘Is this related to a lack of neonatal seizures?’ Cooling is regarded to be an anticonvulsant across the human age spectrum, and we certainly see the warming seizures in hypothermia. But there’s been no conclusive evidence to date that neonatal seizures by themselves are correlated with poorer outcomes in perinatal stroke.”

Dr. Harbert noted that future trials of therapeutic hypothermia for perinatal stroke should include more participants and incorporate different clinical trial designs. “But the key challenge there is going to be identifying your patients with stroke in a timely manner, because most kids with perinatal stroke present with seizure,” she said. “But that’s typically between 12 and 24 hours of life.”

—Colby Stong

AUSTIN—Therapeutic hypothermia may be associated with improved outcomes among children with perinatal stroke and encephalopathy, according to research presented at the 2013 Annual Meeting of the Child Neurology Society.

After receiving therapeutic hypothermia, children with perinatal stroke associated with encephalopathy had an improved neuromotor score at age 12 months and a higher cognitive score at age 30 months compared with those who were not treated with hypothermia, reported Mary Jo Harbert, MD.

“People are often surprised to realize that stroke in newborns is as common as stroke in people over age 65,” said Dr. Harbert, Assistant Clinical Professor, Department of Neurosciences, University of California, San Diego. “There is a disparity in neurology that we don’t have acute therapies for perinatal stroke, whereas we have multiple ones for adult stroke. We’re still actually learning more about outcomes for perinatal stroke. It’s clear to us that a newborn with stroke does not have the same clinical presentation or trajectory as an adult with stroke. We do know, however, that kids with perinatal stroke can present with encephalopathy, which can often lead to the diagnosis of global hypoxic ischemic encephalopathy (HIE), and often these kids are treated as such.”

The Case for Therapeutic Hypothermia
Therapeutic hypothermia has been used to treat multiple neurologic disorders in adults, but the most effective use of it in newborns is in those with HIE, said Dr. Harbert. In 2013, a study in the Cochrane Database of Systematic Reviews found that therapeutic hypothermia reduced deaths and improved long-term neurodevelopmental outcomes for term and late preterm newborns with HIE. In 2011, Dr. Harbert and colleagues presented original data from a prospective cohort of 315 neonates with encephalopathy, in which 15 had had a focal ischemic infarct and five were treated with hypothermia. “Although we demonstrated that the kids with stroke who presented with encephalopathy had much poorer long-term cognitive outcomes than their matched counterparts with HIE, there was another interesting finding during the study—70% of the kids with stroke who had not been cooled had neonatal seizures, whereas of the five kids with stroke who had gotten cooled, none of them had neonatal seizures,” said Dr. Harbert.

Cognitive and Neuromotor Improvement After Hypothermia
In 2013, Dr. Harbert’s group sought to determine whether therapeutic hypothermia was associated with improved cognitive, language, and neuromotor outcomes. The children were followed up at ages 12 months and 30 months, at which point they were assessed with use of the Bayley Scales of Infant Development (BSID-II or Bayley-III) and graded with a neuromotor score.

“When you’re looking at cognitive and language outcomes in particular, the primary issue that had to be overcome first was converting the Bayley-III scores to an equivalent of a Bayley-II,” said Dr. Harbert. “This is because of a common clinical observation that the Bayley-III tends to underestimate the prevalence of developmental delay and overestimate developmental abilities.”

The cohort included 332 children with encephalopathy, of whom 15 had a focal ischemic infarct and five received hypothermia. The group who had received hypothermia had similar clinical characteristics to the group who did not receive hypothermia. “They all had approximately the same gestational age, birth weight, modality of delivery, and encephalopathy score,” said Dr. Harbert.

At 12 months of age, the investigators observed no difference in mean Mental Developmental Index scores between the cooled and untreated groups. At 30 months, however, “the cooled group, on average, performed about 31 points higher than the normothermia group, which is a clinically significant difference, about 2 SD,” said Dr. Harbert.

The hypothermia group had a normal neuromotor examination score (median score, 0) at 12 months, compared with the normothermia group, which, on average, had a neuromotor score of 2 on a scale of 0 to 6.

“We also see the same trend at 30 months,” commented Dr. Harbert. “However, this one was not significant, whereas the 12-month finding was. Again, the normothermia group had an average of a little higher neuromotor score, and the hypothermia group not as much. At the 30-month time point, we were a bit hampered by follow-up attrition. Over 90% of our kids were followed up at 12 months, whereas a little over 70% of our kids were followed up at 30 months. And in such a small series it was a little bit more difficult, especially given the fact that one of our kids who had a stroke tragically passed away in an accidental death.”

A More Compelling Question Than Before
Dr. Harbert pointed out several issues that may have affected her group’s findings. “We definitely had some key challenges in this study, and one of them was the lack of available Bayley conversion algorithms for younger ages at the 12-month time point,” she said. “And then we definitely had an issue with sample size. About 5% of kids within an encephalopathy cohort who are presumed to have HIE actually have perinatal stroke, and this was borne out within our study. We also had some follow-up attrition. And then the last challenge for perinatal stroke and HIE is always the variation in the degree of ischemic injury. Not all strokes are created equal. It’s possible that a variation in the degree of injury could have been responsible for this.

“So at the end of the day, it’s still a question of whether cooling is actually associated with improvement in outcomes in perinatal stroke,” she continued. “But given these findings, it’s a more compelling question than before. It also raises the interesting question of, ‘Is this related to a lack of neonatal seizures?’ Cooling is regarded to be an anticonvulsant across the human age spectrum, and we certainly see the warming seizures in hypothermia. But there’s been no conclusive evidence to date that neonatal seizures by themselves are correlated with poorer outcomes in perinatal stroke.”

Dr. Harbert noted that future trials of therapeutic hypothermia for perinatal stroke should include more participants and incorporate different clinical trial designs. “But the key challenge there is going to be identifying your patients with stroke in a timely manner, because most kids with perinatal stroke present with seizure,” she said. “But that’s typically between 12 and 24 hours of life.”

—Colby Stong

AUSTIN—Therapeutic hypothermia may be associated with improved outcomes among children with perinatal stroke and encephalopathy, according to research presented at the 2013 Annual Meeting of the Child Neurology Society.

After receiving therapeutic hypothermia, children with perinatal stroke associated with encephalopathy had an improved neuromotor score at age 12 months and a higher cognitive score at age 30 months compared with those who were not treated with hypothermia, reported Mary Jo Harbert, MD.

“People are often surprised to realize that stroke in newborns is as common as stroke in people over age 65,” said Dr. Harbert, Assistant Clinical Professor, Department of Neurosciences, University of California, San Diego. “There is a disparity in neurology that we don’t have acute therapies for perinatal stroke, whereas we have multiple ones for adult stroke. We’re still actually learning more about outcomes for perinatal stroke. It’s clear to us that a newborn with stroke does not have the same clinical presentation or trajectory as an adult with stroke. We do know, however, that kids with perinatal stroke can present with encephalopathy, which can often lead to the diagnosis of global hypoxic ischemic encephalopathy (HIE), and often these kids are treated as such.”

The Case for Therapeutic Hypothermia
Therapeutic hypothermia has been used to treat multiple neurologic disorders in adults, but the most effective use of it in newborns is in those with HIE, said Dr. Harbert. In 2013, a study in the Cochrane Database of Systematic Reviews found that therapeutic hypothermia reduced deaths and improved long-term neurodevelopmental outcomes for term and late preterm newborns with HIE. In 2011, Dr. Harbert and colleagues presented original data from a prospective cohort of 315 neonates with encephalopathy, in which 15 had had a focal ischemic infarct and five were treated with hypothermia. “Although we demonstrated that the kids with stroke who presented with encephalopathy had much poorer long-term cognitive outcomes than their matched counterparts with HIE, there was another interesting finding during the study—70% of the kids with stroke who had not been cooled had neonatal seizures, whereas of the five kids with stroke who had gotten cooled, none of them had neonatal seizures,” said Dr. Harbert.

Cognitive and Neuromotor Improvement After Hypothermia
In 2013, Dr. Harbert’s group sought to determine whether therapeutic hypothermia was associated with improved cognitive, language, and neuromotor outcomes. The children were followed up at ages 12 months and 30 months, at which point they were assessed with use of the Bayley Scales of Infant Development (BSID-II or Bayley-III) and graded with a neuromotor score.

“When you’re looking at cognitive and language outcomes in particular, the primary issue that had to be overcome first was converting the Bayley-III scores to an equivalent of a Bayley-II,” said Dr. Harbert. “This is because of a common clinical observation that the Bayley-III tends to underestimate the prevalence of developmental delay and overestimate developmental abilities.”

The cohort included 332 children with encephalopathy, of whom 15 had a focal ischemic infarct and five received hypothermia. The group who had received hypothermia had similar clinical characteristics to the group who did not receive hypothermia. “They all had approximately the same gestational age, birth weight, modality of delivery, and encephalopathy score,” said Dr. Harbert.

At 12 months of age, the investigators observed no difference in mean Mental Developmental Index scores between the cooled and untreated groups. At 30 months, however, “the cooled group, on average, performed about 31 points higher than the normothermia group, which is a clinically significant difference, about 2 SD,” said Dr. Harbert.

The hypothermia group had a normal neuromotor examination score (median score, 0) at 12 months, compared with the normothermia group, which, on average, had a neuromotor score of 2 on a scale of 0 to 6.

“We also see the same trend at 30 months,” commented Dr. Harbert. “However, this one was not significant, whereas the 12-month finding was. Again, the normothermia group had an average of a little higher neuromotor score, and the hypothermia group not as much. At the 30-month time point, we were a bit hampered by follow-up attrition. Over 90% of our kids were followed up at 12 months, whereas a little over 70% of our kids were followed up at 30 months. And in such a small series it was a little bit more difficult, especially given the fact that one of our kids who had a stroke tragically passed away in an accidental death.”

A More Compelling Question Than Before
Dr. Harbert pointed out several issues that may have affected her group’s findings. “We definitely had some key challenges in this study, and one of them was the lack of available Bayley conversion algorithms for younger ages at the 12-month time point,” she said. “And then we definitely had an issue with sample size. About 5% of kids within an encephalopathy cohort who are presumed to have HIE actually have perinatal stroke, and this was borne out within our study. We also had some follow-up attrition. And then the last challenge for perinatal stroke and HIE is always the variation in the degree of ischemic injury. Not all strokes are created equal. It’s possible that a variation in the degree of injury could have been responsible for this.

“So at the end of the day, it’s still a question of whether cooling is actually associated with improvement in outcomes in perinatal stroke,” she continued. “But given these findings, it’s a more compelling question than before. It also raises the interesting question of, ‘Is this related to a lack of neonatal seizures?’ Cooling is regarded to be an anticonvulsant across the human age spectrum, and we certainly see the warming seizures in hypothermia. But there’s been no conclusive evidence to date that neonatal seizures by themselves are correlated with poorer outcomes in perinatal stroke.”

Dr. Harbert noted that future trials of therapeutic hypothermia for perinatal stroke should include more participants and incorporate different clinical trial designs. “But the key challenge there is going to be identifying your patients with stroke in a timely manner, because most kids with perinatal stroke present with seizure,” she said. “But that’s typically between 12 and 24 hours of life.”

—Colby Stong