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Headache may be a significant outcome of pediatric hemispherectomy
CHARLOTTE, N.C. – , according to a study presented at the annual meeting of the Child Neurology Society. Patients with headache before hemispherectomy may be at risk of increased headache frequency after the procedure. The most common type of headache reported is nonmigrainous headache.
“We recommend that hemispherectomy patients be evaluated and followed closely postoperatively and questioned regarding the presence of headache,” said William Bingaman, MD, vice-chair of the neurological institute and head of the section of epilepsy surgery at the Cleveland Clinic, and colleagues. “Patients should be assessed and treated quickly to decrease prolonged pain and suffering and increase function.”
The two main types of hemispherectomy are anatomical and functional. Anatomical hemispherectomy entails the removal of a large amount of brain mass. Functional hemispherectomy entails the removal of a smaller amount of brain mass, as well as the disconnection of the brain’s hemispheres. Most patients are seizure free or have reduced seizure frequency after hemispherectomy. Other common postoperative outcomes include changes in behavior, cognition, motor function, and speech. Many studies have explored these outcomes, but few have examined the frequency of postoperative headache in children who undergo hemispherectomy.
Dr. Bingaman and colleagues retrospectively reviewed the charts of 74 children who underwent hemispherectomy at the Cleveland Clinic during the previous 5 years. They excluded 14 patients who were too young to respond for the analysis. The investigators sent the remaining 60 patients an informative letter and followed up with a 10-minute phone questionnaire about patients’ postoperative headache symptoms.
Twenty-two (36.7%) eligible patients completed the questionnaire. Thirty-eight patients could not be reached or declined to participate. Half of the 22 respondents were male. Participants’ median age at surgery was 6.5 years. The most common types of hemispherectomy were left functional (50%) and right functional (31.8%).
Nine (39.1%) of the 22 respondents had headache before surgery, and seven (31.8%) reported a family history of headache. In all, 19 (86.4%) patients had headache after surgery, and 10 (45.5%) had headaches that began after the surgery. Of the nine patients with preoperative headache, six (66.6%) had an increase in headache frequency after surgery, two (22.2%) reported no change, and one (11.1%) had decreased headache frequency. The most common type of headache reported was tension-type headache, and migraine was the second most common.
“The cause of any posthemispherectomy headache has thus far only been attributed to hydrocephalus,” wrote Dr. Bingaman and colleagues. “The tendency of headache to worsen following stresses such as illness, stroke, trauma, etc. has been studied extensively. The pathophysiology of posthemispherectomy headache can be investigated further by classifying hemispherectomy as a type of trauma or injury, which would explain the development of postoperative headache. Previous studies on posttraumatic headache have ascribed these headaches to neuroinflammation following the injury. Additionally, posthemispherectomy headache could also be due to the buildup of debris and fluid following the operation. Future hemispherectomy patients should be treated prophylactically for headache.”
The authors did not report funding for their study or declare any disclosures.
SOURCE: Pandit I et al. CNS 2019. Abstract 99.
CHARLOTTE, N.C. – , according to a study presented at the annual meeting of the Child Neurology Society. Patients with headache before hemispherectomy may be at risk of increased headache frequency after the procedure. The most common type of headache reported is nonmigrainous headache.
“We recommend that hemispherectomy patients be evaluated and followed closely postoperatively and questioned regarding the presence of headache,” said William Bingaman, MD, vice-chair of the neurological institute and head of the section of epilepsy surgery at the Cleveland Clinic, and colleagues. “Patients should be assessed and treated quickly to decrease prolonged pain and suffering and increase function.”
The two main types of hemispherectomy are anatomical and functional. Anatomical hemispherectomy entails the removal of a large amount of brain mass. Functional hemispherectomy entails the removal of a smaller amount of brain mass, as well as the disconnection of the brain’s hemispheres. Most patients are seizure free or have reduced seizure frequency after hemispherectomy. Other common postoperative outcomes include changes in behavior, cognition, motor function, and speech. Many studies have explored these outcomes, but few have examined the frequency of postoperative headache in children who undergo hemispherectomy.
Dr. Bingaman and colleagues retrospectively reviewed the charts of 74 children who underwent hemispherectomy at the Cleveland Clinic during the previous 5 years. They excluded 14 patients who were too young to respond for the analysis. The investigators sent the remaining 60 patients an informative letter and followed up with a 10-minute phone questionnaire about patients’ postoperative headache symptoms.
Twenty-two (36.7%) eligible patients completed the questionnaire. Thirty-eight patients could not be reached or declined to participate. Half of the 22 respondents were male. Participants’ median age at surgery was 6.5 years. The most common types of hemispherectomy were left functional (50%) and right functional (31.8%).
Nine (39.1%) of the 22 respondents had headache before surgery, and seven (31.8%) reported a family history of headache. In all, 19 (86.4%) patients had headache after surgery, and 10 (45.5%) had headaches that began after the surgery. Of the nine patients with preoperative headache, six (66.6%) had an increase in headache frequency after surgery, two (22.2%) reported no change, and one (11.1%) had decreased headache frequency. The most common type of headache reported was tension-type headache, and migraine was the second most common.
“The cause of any posthemispherectomy headache has thus far only been attributed to hydrocephalus,” wrote Dr. Bingaman and colleagues. “The tendency of headache to worsen following stresses such as illness, stroke, trauma, etc. has been studied extensively. The pathophysiology of posthemispherectomy headache can be investigated further by classifying hemispherectomy as a type of trauma or injury, which would explain the development of postoperative headache. Previous studies on posttraumatic headache have ascribed these headaches to neuroinflammation following the injury. Additionally, posthemispherectomy headache could also be due to the buildup of debris and fluid following the operation. Future hemispherectomy patients should be treated prophylactically for headache.”
The authors did not report funding for their study or declare any disclosures.
SOURCE: Pandit I et al. CNS 2019. Abstract 99.
CHARLOTTE, N.C. – , according to a study presented at the annual meeting of the Child Neurology Society. Patients with headache before hemispherectomy may be at risk of increased headache frequency after the procedure. The most common type of headache reported is nonmigrainous headache.
“We recommend that hemispherectomy patients be evaluated and followed closely postoperatively and questioned regarding the presence of headache,” said William Bingaman, MD, vice-chair of the neurological institute and head of the section of epilepsy surgery at the Cleveland Clinic, and colleagues. “Patients should be assessed and treated quickly to decrease prolonged pain and suffering and increase function.”
The two main types of hemispherectomy are anatomical and functional. Anatomical hemispherectomy entails the removal of a large amount of brain mass. Functional hemispherectomy entails the removal of a smaller amount of brain mass, as well as the disconnection of the brain’s hemispheres. Most patients are seizure free or have reduced seizure frequency after hemispherectomy. Other common postoperative outcomes include changes in behavior, cognition, motor function, and speech. Many studies have explored these outcomes, but few have examined the frequency of postoperative headache in children who undergo hemispherectomy.
Dr. Bingaman and colleagues retrospectively reviewed the charts of 74 children who underwent hemispherectomy at the Cleveland Clinic during the previous 5 years. They excluded 14 patients who were too young to respond for the analysis. The investigators sent the remaining 60 patients an informative letter and followed up with a 10-minute phone questionnaire about patients’ postoperative headache symptoms.
Twenty-two (36.7%) eligible patients completed the questionnaire. Thirty-eight patients could not be reached or declined to participate. Half of the 22 respondents were male. Participants’ median age at surgery was 6.5 years. The most common types of hemispherectomy were left functional (50%) and right functional (31.8%).
Nine (39.1%) of the 22 respondents had headache before surgery, and seven (31.8%) reported a family history of headache. In all, 19 (86.4%) patients had headache after surgery, and 10 (45.5%) had headaches that began after the surgery. Of the nine patients with preoperative headache, six (66.6%) had an increase in headache frequency after surgery, two (22.2%) reported no change, and one (11.1%) had decreased headache frequency. The most common type of headache reported was tension-type headache, and migraine was the second most common.
“The cause of any posthemispherectomy headache has thus far only been attributed to hydrocephalus,” wrote Dr. Bingaman and colleagues. “The tendency of headache to worsen following stresses such as illness, stroke, trauma, etc. has been studied extensively. The pathophysiology of posthemispherectomy headache can be investigated further by classifying hemispherectomy as a type of trauma or injury, which would explain the development of postoperative headache. Previous studies on posttraumatic headache have ascribed these headaches to neuroinflammation following the injury. Additionally, posthemispherectomy headache could also be due to the buildup of debris and fluid following the operation. Future hemispherectomy patients should be treated prophylactically for headache.”
The authors did not report funding for their study or declare any disclosures.
SOURCE: Pandit I et al. CNS 2019. Abstract 99.
REPORTING FROM CNS 2019
Children may develop prolonged headache after concussion
CHARLOTTE, N.C. – , according to research presented at the annual meeting of the Child Neurology Society. The headache may be migraine, chronic daily headache, tension-type headache, or a combination of these headaches.
“We strongly recommend that individuals who develop persistent headache after a concussion be evaluated and treated by a neurologist with experience in administering treatment for headache,” said Marcus Barissi, Weller Scholar at the Cleveland Clinic, and colleagues. “Using this approach, we hope that their prolonged headaches will be lessened.”
Few studies have examined prolonged pediatric postconcussion headache
The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur annually during athletic and recreational activities in the United States. About 90% of concussions affect children or adolescents. The symptom most often reported after concussion is headache.
Few studies have focused on new persistent postconcussion headache (NPPCH) in children. Mr. Barissi and colleagues did not find any previous study that had examined prolonged headache following concussion in patients without prior chronic headache. They sought to ascertain the prognosis of patients with NPPCH and no history of prior headache, to describe this clinical entity, and to identify beneficial treatment methods.
The investigators retrospectively reviewed charts for approximately 2,000 patients who presented to the Cleveland Clinic pediatric neurology department between June 2017 and August 2018 for headaches. They identified 259 patients who received a diagnosis of concussion, 69 (27%) of whom had headaches for longer than 2 months after injury.
Mr. Barissi and colleagues emailed these patients, and 33 (48%) of them agreed to complete a questionnaire and participate in a 10-minute phone interview. Thirty-one patients (43%) could not be contacted, and eight (11%) declined to participate. All participants confirmed that they had not had consistent headache before the concussion and that chronic headache had arisen after concussion. To determine participants’ medical outcomes, the researchers compared participants’ initial assessment data with posttreatment data collected during the interview process.
Healthy behaviors increased after concussion
Of the 69 eligible participants, 38 (55%) were female. The population’s median age was 17. Twenty-eight (85%) of the 33 patients who completed the questionnaire considered the information and treatment that they had received to be beneficial. Twenty-five (78%) patients continued to have headache after several months, despite treatment.
Participants had withstood a mean of 1.72 concussions, and the mean age at first injury was 12.49 years. The most common cause of injury was a fall for males (36%) and an automobile accident for females (18%).
Forty-eight patients (70%) reported having two types of headache. Fifty-two patients (75%) had migraines, and 65 (94%) had chronic daily headache or tension-type headache. Forty-eight (70%) participants had a family history of headache.
In all, 64 patients (93%) had used a headache medication. The most common headache medications used were amitriptyline, topiramate, and cyproheptadine. Few patients were still taking these medications at several months after evaluation. The most common nonprescription medications used were Migravent (i.e., magnesium, riboflavin, coenzyme Q10, and butterbur), ondansetron, and melatonin. Furthermore, 61 patients (88%) participated in nonmedicinal therapy such as physical therapy, chiropractic therapy, and acupuncture.
After evaluation, patients engaged in several healthy behaviors (e.g., adequate exercise, proper use of over-the-counter medications, and drinking sufficient water) more frequently, but did not get adequate sleep. Sixty-five participants (94%) had undergone CT or MRI imaging, but the results did not improve understanding of headache etiology or treatment. Many patients missed several days of school, but average attendance improved after months of treatment.
Long-term outcomes
Thirty-one survey respondents (94%) reported that their emotional, cognitive, sleep, and somatic postconcussion symptoms had resolved. Nevertheless, a majority of participants still had headache. “The persistence of postconcussion symptoms is uncommon, but lasting headache is not,” said the researchers. “If patients are not properly educated, conditions may deteriorate, extending the duration of disability.” A longer study with a larger sample size could provide valuable information, said the researchers. Future work should examine objectively the efficacy of various medications used to treat NPPCH and determine the best methods of treatment for this syndrome, which “can cause prolonged pain, suffering, and lack of function,” they concluded.
The investigators did not report any study funding or disclosures.
SOURCE: Barissi M et al. CNS 2019, Abstract 95.
CHARLOTTE, N.C. – , according to research presented at the annual meeting of the Child Neurology Society. The headache may be migraine, chronic daily headache, tension-type headache, or a combination of these headaches.
“We strongly recommend that individuals who develop persistent headache after a concussion be evaluated and treated by a neurologist with experience in administering treatment for headache,” said Marcus Barissi, Weller Scholar at the Cleveland Clinic, and colleagues. “Using this approach, we hope that their prolonged headaches will be lessened.”
Few studies have examined prolonged pediatric postconcussion headache
The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur annually during athletic and recreational activities in the United States. About 90% of concussions affect children or adolescents. The symptom most often reported after concussion is headache.
Few studies have focused on new persistent postconcussion headache (NPPCH) in children. Mr. Barissi and colleagues did not find any previous study that had examined prolonged headache following concussion in patients without prior chronic headache. They sought to ascertain the prognosis of patients with NPPCH and no history of prior headache, to describe this clinical entity, and to identify beneficial treatment methods.
The investigators retrospectively reviewed charts for approximately 2,000 patients who presented to the Cleveland Clinic pediatric neurology department between June 2017 and August 2018 for headaches. They identified 259 patients who received a diagnosis of concussion, 69 (27%) of whom had headaches for longer than 2 months after injury.
Mr. Barissi and colleagues emailed these patients, and 33 (48%) of them agreed to complete a questionnaire and participate in a 10-minute phone interview. Thirty-one patients (43%) could not be contacted, and eight (11%) declined to participate. All participants confirmed that they had not had consistent headache before the concussion and that chronic headache had arisen after concussion. To determine participants’ medical outcomes, the researchers compared participants’ initial assessment data with posttreatment data collected during the interview process.
Healthy behaviors increased after concussion
Of the 69 eligible participants, 38 (55%) were female. The population’s median age was 17. Twenty-eight (85%) of the 33 patients who completed the questionnaire considered the information and treatment that they had received to be beneficial. Twenty-five (78%) patients continued to have headache after several months, despite treatment.
Participants had withstood a mean of 1.72 concussions, and the mean age at first injury was 12.49 years. The most common cause of injury was a fall for males (36%) and an automobile accident for females (18%).
Forty-eight patients (70%) reported having two types of headache. Fifty-two patients (75%) had migraines, and 65 (94%) had chronic daily headache or tension-type headache. Forty-eight (70%) participants had a family history of headache.
In all, 64 patients (93%) had used a headache medication. The most common headache medications used were amitriptyline, topiramate, and cyproheptadine. Few patients were still taking these medications at several months after evaluation. The most common nonprescription medications used were Migravent (i.e., magnesium, riboflavin, coenzyme Q10, and butterbur), ondansetron, and melatonin. Furthermore, 61 patients (88%) participated in nonmedicinal therapy such as physical therapy, chiropractic therapy, and acupuncture.
After evaluation, patients engaged in several healthy behaviors (e.g., adequate exercise, proper use of over-the-counter medications, and drinking sufficient water) more frequently, but did not get adequate sleep. Sixty-five participants (94%) had undergone CT or MRI imaging, but the results did not improve understanding of headache etiology or treatment. Many patients missed several days of school, but average attendance improved after months of treatment.
Long-term outcomes
Thirty-one survey respondents (94%) reported that their emotional, cognitive, sleep, and somatic postconcussion symptoms had resolved. Nevertheless, a majority of participants still had headache. “The persistence of postconcussion symptoms is uncommon, but lasting headache is not,” said the researchers. “If patients are not properly educated, conditions may deteriorate, extending the duration of disability.” A longer study with a larger sample size could provide valuable information, said the researchers. Future work should examine objectively the efficacy of various medications used to treat NPPCH and determine the best methods of treatment for this syndrome, which “can cause prolonged pain, suffering, and lack of function,” they concluded.
The investigators did not report any study funding or disclosures.
SOURCE: Barissi M et al. CNS 2019, Abstract 95.
CHARLOTTE, N.C. – , according to research presented at the annual meeting of the Child Neurology Society. The headache may be migraine, chronic daily headache, tension-type headache, or a combination of these headaches.
“We strongly recommend that individuals who develop persistent headache after a concussion be evaluated and treated by a neurologist with experience in administering treatment for headache,” said Marcus Barissi, Weller Scholar at the Cleveland Clinic, and colleagues. “Using this approach, we hope that their prolonged headaches will be lessened.”
Few studies have examined prolonged pediatric postconcussion headache
The Centers for Disease Control and Prevention estimates that between 1.6 million and 3.8 million concussions occur annually during athletic and recreational activities in the United States. About 90% of concussions affect children or adolescents. The symptom most often reported after concussion is headache.
Few studies have focused on new persistent postconcussion headache (NPPCH) in children. Mr. Barissi and colleagues did not find any previous study that had examined prolonged headache following concussion in patients without prior chronic headache. They sought to ascertain the prognosis of patients with NPPCH and no history of prior headache, to describe this clinical entity, and to identify beneficial treatment methods.
The investigators retrospectively reviewed charts for approximately 2,000 patients who presented to the Cleveland Clinic pediatric neurology department between June 2017 and August 2018 for headaches. They identified 259 patients who received a diagnosis of concussion, 69 (27%) of whom had headaches for longer than 2 months after injury.
Mr. Barissi and colleagues emailed these patients, and 33 (48%) of them agreed to complete a questionnaire and participate in a 10-minute phone interview. Thirty-one patients (43%) could not be contacted, and eight (11%) declined to participate. All participants confirmed that they had not had consistent headache before the concussion and that chronic headache had arisen after concussion. To determine participants’ medical outcomes, the researchers compared participants’ initial assessment data with posttreatment data collected during the interview process.
Healthy behaviors increased after concussion
Of the 69 eligible participants, 38 (55%) were female. The population’s median age was 17. Twenty-eight (85%) of the 33 patients who completed the questionnaire considered the information and treatment that they had received to be beneficial. Twenty-five (78%) patients continued to have headache after several months, despite treatment.
Participants had withstood a mean of 1.72 concussions, and the mean age at first injury was 12.49 years. The most common cause of injury was a fall for males (36%) and an automobile accident for females (18%).
Forty-eight patients (70%) reported having two types of headache. Fifty-two patients (75%) had migraines, and 65 (94%) had chronic daily headache or tension-type headache. Forty-eight (70%) participants had a family history of headache.
In all, 64 patients (93%) had used a headache medication. The most common headache medications used were amitriptyline, topiramate, and cyproheptadine. Few patients were still taking these medications at several months after evaluation. The most common nonprescription medications used were Migravent (i.e., magnesium, riboflavin, coenzyme Q10, and butterbur), ondansetron, and melatonin. Furthermore, 61 patients (88%) participated in nonmedicinal therapy such as physical therapy, chiropractic therapy, and acupuncture.
After evaluation, patients engaged in several healthy behaviors (e.g., adequate exercise, proper use of over-the-counter medications, and drinking sufficient water) more frequently, but did not get adequate sleep. Sixty-five participants (94%) had undergone CT or MRI imaging, but the results did not improve understanding of headache etiology or treatment. Many patients missed several days of school, but average attendance improved after months of treatment.
Long-term outcomes
Thirty-one survey respondents (94%) reported that their emotional, cognitive, sleep, and somatic postconcussion symptoms had resolved. Nevertheless, a majority of participants still had headache. “The persistence of postconcussion symptoms is uncommon, but lasting headache is not,” said the researchers. “If patients are not properly educated, conditions may deteriorate, extending the duration of disability.” A longer study with a larger sample size could provide valuable information, said the researchers. Future work should examine objectively the efficacy of various medications used to treat NPPCH and determine the best methods of treatment for this syndrome, which “can cause prolonged pain, suffering, and lack of function,” they concluded.
The investigators did not report any study funding or disclosures.
SOURCE: Barissi M et al. CNS 2019, Abstract 95.
REPORTING FROM CNS 2019
AVXS-101 may result in long-term motor improvements in SMA
CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.
SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.
AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.
At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.
Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.
Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
SOURCE: Dabbous O et al. CNS 2019. Abstract 199.
CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.
SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.
AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.
At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.
Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.
Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
SOURCE: Dabbous O et al. CNS 2019. Abstract 199.
CHARLOTTE, N.C. – AVXS-101, the Food and Drug Administration–approved therapy for spinal muscular atrophy (SMA), yields rapid, sustained improvements in CHOP INTEND scores, better survival, and motor function improvements at long-term follow-up, according to an analysis presented at the annual meeting of the Child Neurology Society. The results provide a clinical demonstration of continuous expression of the SMN protein, according to the investigators. In addition, AVXS-101 is associated with reduced health care utilization in treated infants, which could decrease costs, lessen the burden on patients and caregivers, and improve quality of life.
SMA1 is a progressive neurologic disease that causes loss of the lower motor neurons in the spinal cord and brainstem. Patients have increasing muscle weakness that leads to death or the need for permanent ventilation by age 2 years. The disease results from mutations in the SMN1 gene. AVXS-101 replaces the missing or nonfunctional SMN1 with a healthy copy of a human SMN gene.
AveXis, the company that developed the therapy, enrolled 12 patients with SMA1 in a phase 1/2a study between December 2014 and December 2015. All participants received one intravenous infusion of AVXS-101. Omar Dabbous, MD, vice president of global health economics, outcomes research, and real world evidence at AveXis in Bannockburn, Ill., and colleagues evaluated participants’ rates of event-free survival (i.e., absence of death or need for permanent ventilation), pulmonary or nutritional interventions, swallowing, hospitalization, and CHOP INTEND scores, as well as therapeutic safety at 2 years.
At study completion, all patients who had received a therapeutic dose had event-free survival. Seven participants did not need daily noninvasive ventilation. Eleven participants had stable or improved swallowing. All of the latter patients fed orally, and six fed exclusively by mouth. Eleven patients spoke.
Participants had a mean of 1.4 respiratory hospitalizations per year. Mean proportion of time participants spent hospitalized was 4.4%. Mean hospitalization rate per year was 2.1, and mean length of hospital stay was 6.7 days. In addition, participants’ CHOP INTEND scores increased from baseline by 9.8 points at 1 month and by 15.4 points at 3 months. Patients who received a therapeutic dose of AVXS-101 have maintained their motor milestones at long-term follow-up, which suggests that treatment effects persist over the long term. Adverse events included elevated serum aminotransferase levels, which were reduced by prednisolone.
Dr. Dabbous is an employee of AveXis, which developed AVXS-101.
SOURCE: Dabbous O et al. CNS 2019. Abstract 199.
REPORTING FROM CNS 2019
Stroke is diagnosed in about one-fifth of children with strokelike symptoms
CHARLOTTE, N.C. – (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.
Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.
“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”
In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.
Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.
These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”
The investigators did not have funding for this study and did not report any disclosures.
SOURCE: Barkley T et al. CNS 2019. Abstract 235.
CHARLOTTE, N.C. – (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.
Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.
“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”
In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.
Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.
These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”
The investigators did not have funding for this study and did not report any disclosures.
SOURCE: Barkley T et al. CNS 2019. Abstract 235.
CHARLOTTE, N.C. – (TIA), according to research presented at the annual meeting of the Child Neurology Society. Ischemic stroke and TIA were the second leading diagnoses among the stroke activations examined in the study, after seizure and Todd’s paralysis. “These data, in conjunction with previous studies, highlight the importance of developing protocols for early recognition and evaluation of children who present with strokelike symptoms,” said Tiffany Barkley, DO, a child neurology resident at Children’s Mercy Hospital in Kansas City, Mo., and colleagues.
Dr. Barkley and colleagues conducted their research to describe the demographic and other characteristics of patients who present with strokelike symptoms to their hospital. They undertook a descriptive, retrospective chart review of patients who came to Children’s Mercy Hospital from Sept. 1, 2016, to August 31, 2018, with concern for acute stroke. The investigators examined only patients for whom the Stroke Alert Process and power plan were activated.
“Power plans were created at Children’s Mercy Hospital to streamline and standardize care for children,” said Dr. Barkley. “While stroke order sets tend to be common practice in many adult hospitals, stroke order sets in pediatric hospitals are new.”
In all, 61 stroke activations occurred during the study period. Twelve patients (20%) had a final diagnosis of ischemic stroke or TIA. Among the patients with a final diagnosis of ischemic stroke, the most common presenting symptom was unilateral weakness. Two of these patients were candidates for intervention with mechanical thrombectomy, and none received tissue plasminogen activator. The average age of patients in all activations was 14 years, and the average age of patients with a final diagnosis of ischemic stroke or TIA was 4 years. About 37 (61%) subjects of activations were female, and the most common racial demographic was Caucasian.
Ischemic stroke or TIA was the second most common diagnosis of all activations (12 patients; 20%). Seizure or Todd’s paralysis (14 patients; 23%) was the leading diagnosis. Other common diagnoses included migraine (18%), psychogenic or conversion disorder (15%), oncologic process (3.0%), and complications of meningitis or encephalitis (1.6%). Children who presented with ischemic stroke secondary to Moyamoya disease were classified separately (two patients or 3%). It can be difficult to distinguish between stroke and stroke mimics based on neurologic examination alone, and imaging such as MRI often is needed, said Dr. Barkley. The researchers did not identify any intracranial hemorrhages in this patient population.
These findings are consistent with current reported literature, said the researchers. “Our study is one of the first to look at the demographics of children who present with strokelike symptoms,” said Dr. Barkley. “We hope that our study will not only help identify children who present with symptoms concerning for stroke, but also help us identify children who may be at risk for ischemic stroke before the stroke happens.”
The investigators did not have funding for this study and did not report any disclosures.
SOURCE: Barkley T et al. CNS 2019. Abstract 235.
REPORTING FROM CNS 2019
Fetal MRI may change pregnancy management
CHARLOTTE, N.C. – according to research presented at the annual meeting of the Child Neurology Society. This imaging technique and neurologic consultation complement the information that prenatal ultrasound and obstetric consultations provide and may influence pregnancy management and infant neurologic care significantly.
The fetal diagnosis of posterior fossa abnormalities can be challenging. The prognosis can vary greatly, depending on the diagnosis. Sarah Mulkey, MD, PhD, director of the fetal and neonatal fellowship and a fetal and neonatal neurologist at Children’s National in Washington, and colleagues conducted an analysis to evaluate whether fetal MRI and neurology consultation produce alternative diagnoses for maternal-fetal dyads who are referred to a fetal neurology program because of concern for a fetal posterior fossa anomaly. The researchers also sought to determine how often the postnatal evaluation differed from the fetal diagnosis.
Dr. Mulkey and colleagues retrospectively analyzed cases referred to the Fetal Medicine Institute at Children’s National from January 2012 to June 2018. They included the referral diagnoses of Dandy-Walker continuum, cerebellar hypoplasia, vermis hypoplasia, Blake’s pouch cyst, mega cisterna magna, and other posterior fossa anomalies in their study.
The investigators identified 188 cases that had undergone fetal MRI and neurology consultation. The average gestational age at evaluation was 25 weeks, and the average maternal age was 30 years. Approximately 43% of referrals resulted from a concern regarding Dandy-Walker malformation, and 21% of referrals resulted from a suspicion of mega cisterna magna.
Fetal MRI and neurology consultation resulted in a change from the referral diagnosis or additional information about the fetus in 124 (66%) cases. For example, after imaging and consultation, 15% of referrals were diagnosed with Dandy-Walker malformation, as opposed to the 43% who were suspected of having it. Most referrals with a diagnosis of vermis hypoplasia had a better prognosis after fetal MRI. Fetal MRI and consultation also resulted in new diagnoses of Joubert syndrome and rhombencephalosynapsis. About 19% of referrals were considered normal. “A considerable number of these referrals ended up being for conditions that would have a good outcome,” said Dr. Mulkey.
In addition, the researchers obtained the postnatal diagnosis for 60 of 138 (43%) live-born infants. The fetal diagnosis of Dandy-Walker continuum was confirmed post natally in six of six (100%) cases. Of the 13 cases of fetally diagnosed vermis hypoplasia, 7 (54%) had stable findings, 3 (23%) normalized, and diagnosis changed in 3 (23%). Of the 17 fetally diagnosed Blake’s pouch cysts, 8 (47%) remained stable, 5 (29%) normalized, and diagnosis changed in 4 (24%). Four of nine (44%) cases of fetally diagnosed mega cisterna magna remained stable, two (22%) normalized, and diagnosis changed in three (33%). Overall, prognosis did not change after postnatal imaging.
“There is a high degree of correlation between fetal and postnatal diagnoses for Dandy-Walker continuum, cerebellar hypoplasia, cyst, and ‘other’ diagnoses,” said Dr. Mulkey. “Vermis hypoplasia and Blake’s pouch cyst diagnoses were less consistent.”
The investigators reported no disclosures.
SOURCE: Schlatterer S et al. CNS 2019, Abstract 158.
CHARLOTTE, N.C. – according to research presented at the annual meeting of the Child Neurology Society. This imaging technique and neurologic consultation complement the information that prenatal ultrasound and obstetric consultations provide and may influence pregnancy management and infant neurologic care significantly.
The fetal diagnosis of posterior fossa abnormalities can be challenging. The prognosis can vary greatly, depending on the diagnosis. Sarah Mulkey, MD, PhD, director of the fetal and neonatal fellowship and a fetal and neonatal neurologist at Children’s National in Washington, and colleagues conducted an analysis to evaluate whether fetal MRI and neurology consultation produce alternative diagnoses for maternal-fetal dyads who are referred to a fetal neurology program because of concern for a fetal posterior fossa anomaly. The researchers also sought to determine how often the postnatal evaluation differed from the fetal diagnosis.
Dr. Mulkey and colleagues retrospectively analyzed cases referred to the Fetal Medicine Institute at Children’s National from January 2012 to June 2018. They included the referral diagnoses of Dandy-Walker continuum, cerebellar hypoplasia, vermis hypoplasia, Blake’s pouch cyst, mega cisterna magna, and other posterior fossa anomalies in their study.
The investigators identified 188 cases that had undergone fetal MRI and neurology consultation. The average gestational age at evaluation was 25 weeks, and the average maternal age was 30 years. Approximately 43% of referrals resulted from a concern regarding Dandy-Walker malformation, and 21% of referrals resulted from a suspicion of mega cisterna magna.
Fetal MRI and neurology consultation resulted in a change from the referral diagnosis or additional information about the fetus in 124 (66%) cases. For example, after imaging and consultation, 15% of referrals were diagnosed with Dandy-Walker malformation, as opposed to the 43% who were suspected of having it. Most referrals with a diagnosis of vermis hypoplasia had a better prognosis after fetal MRI. Fetal MRI and consultation also resulted in new diagnoses of Joubert syndrome and rhombencephalosynapsis. About 19% of referrals were considered normal. “A considerable number of these referrals ended up being for conditions that would have a good outcome,” said Dr. Mulkey.
In addition, the researchers obtained the postnatal diagnosis for 60 of 138 (43%) live-born infants. The fetal diagnosis of Dandy-Walker continuum was confirmed post natally in six of six (100%) cases. Of the 13 cases of fetally diagnosed vermis hypoplasia, 7 (54%) had stable findings, 3 (23%) normalized, and diagnosis changed in 3 (23%). Of the 17 fetally diagnosed Blake’s pouch cysts, 8 (47%) remained stable, 5 (29%) normalized, and diagnosis changed in 4 (24%). Four of nine (44%) cases of fetally diagnosed mega cisterna magna remained stable, two (22%) normalized, and diagnosis changed in three (33%). Overall, prognosis did not change after postnatal imaging.
“There is a high degree of correlation between fetal and postnatal diagnoses for Dandy-Walker continuum, cerebellar hypoplasia, cyst, and ‘other’ diagnoses,” said Dr. Mulkey. “Vermis hypoplasia and Blake’s pouch cyst diagnoses were less consistent.”
The investigators reported no disclosures.
SOURCE: Schlatterer S et al. CNS 2019, Abstract 158.
CHARLOTTE, N.C. – according to research presented at the annual meeting of the Child Neurology Society. This imaging technique and neurologic consultation complement the information that prenatal ultrasound and obstetric consultations provide and may influence pregnancy management and infant neurologic care significantly.
The fetal diagnosis of posterior fossa abnormalities can be challenging. The prognosis can vary greatly, depending on the diagnosis. Sarah Mulkey, MD, PhD, director of the fetal and neonatal fellowship and a fetal and neonatal neurologist at Children’s National in Washington, and colleagues conducted an analysis to evaluate whether fetal MRI and neurology consultation produce alternative diagnoses for maternal-fetal dyads who are referred to a fetal neurology program because of concern for a fetal posterior fossa anomaly. The researchers also sought to determine how often the postnatal evaluation differed from the fetal diagnosis.
Dr. Mulkey and colleagues retrospectively analyzed cases referred to the Fetal Medicine Institute at Children’s National from January 2012 to June 2018. They included the referral diagnoses of Dandy-Walker continuum, cerebellar hypoplasia, vermis hypoplasia, Blake’s pouch cyst, mega cisterna magna, and other posterior fossa anomalies in their study.
The investigators identified 188 cases that had undergone fetal MRI and neurology consultation. The average gestational age at evaluation was 25 weeks, and the average maternal age was 30 years. Approximately 43% of referrals resulted from a concern regarding Dandy-Walker malformation, and 21% of referrals resulted from a suspicion of mega cisterna magna.
Fetal MRI and neurology consultation resulted in a change from the referral diagnosis or additional information about the fetus in 124 (66%) cases. For example, after imaging and consultation, 15% of referrals were diagnosed with Dandy-Walker malformation, as opposed to the 43% who were suspected of having it. Most referrals with a diagnosis of vermis hypoplasia had a better prognosis after fetal MRI. Fetal MRI and consultation also resulted in new diagnoses of Joubert syndrome and rhombencephalosynapsis. About 19% of referrals were considered normal. “A considerable number of these referrals ended up being for conditions that would have a good outcome,” said Dr. Mulkey.
In addition, the researchers obtained the postnatal diagnosis for 60 of 138 (43%) live-born infants. The fetal diagnosis of Dandy-Walker continuum was confirmed post natally in six of six (100%) cases. Of the 13 cases of fetally diagnosed vermis hypoplasia, 7 (54%) had stable findings, 3 (23%) normalized, and diagnosis changed in 3 (23%). Of the 17 fetally diagnosed Blake’s pouch cysts, 8 (47%) remained stable, 5 (29%) normalized, and diagnosis changed in 4 (24%). Four of nine (44%) cases of fetally diagnosed mega cisterna magna remained stable, two (22%) normalized, and diagnosis changed in three (33%). Overall, prognosis did not change after postnatal imaging.
“There is a high degree of correlation between fetal and postnatal diagnoses for Dandy-Walker continuum, cerebellar hypoplasia, cyst, and ‘other’ diagnoses,” said Dr. Mulkey. “Vermis hypoplasia and Blake’s pouch cyst diagnoses were less consistent.”
The investigators reported no disclosures.
SOURCE: Schlatterer S et al. CNS 2019, Abstract 158.
REPORTING FROM CNS 2019
Edasalonexent may slow progression of Duchenne muscular dystrophy
CHARLOTTE, N.C. – presented at the annual meeting of the Child Neurology Society.
The NF-kB pathway is “fundamental to the pathogenesis and biology of DMD,” said Richard Finkel, MD, chief of neurology at Nemours Children’s Health System in Orlando and principal investigator for the phase 2 study, known as MoveDMD.
A lack of dystrophin, combined with the mechanical stress of muscle contraction, activates the NF-kB pathway and inhibits muscle regeneration. “It is known that there is inflammation and fibrosis and release of cytokines early in life” in patients with DMD, Dr. Finkel said.
Independent of mutation
Edasalonexent is an NF-kB inhibitor that is being developed by Catabasis as a therapy for patients with DMD regardless of the genetic mutation that is causing the disease. It may be used as monotherapy or with other dystrophin-targeted treatments, Dr. Finkel said.
In a mouse model of DMD, an analog of the drug reduced muscle inflammation and increased the force of diaphragm muscle. To assess edasalonexent’s safety, pharmacokinetics, and effects on functional measures and MRI in patients with DMD, Dr. Finkel and colleagues conducted the MoveDMD trial. Investigators enrolled boys aged 4 years to younger than 8 years who were not receiving treatment with corticosteroids.
Researchers first examined drug safety and pharmacokinetics in 17 boys who received the treatment for 1 week. The investigators then followed 16 of these patients off treatment for as long as 6 months. This off-treatment period was followed by a phase 2, placebo-controlled period, during which the 16 patients and another 15 patients received edasalonexent 67 mg/kg/day, edasalonexent 100 mg/kg/day, or placebo for 12 weeks. Patients subsequently entered an open-label extension study.
Dr. Finkel presented a comparison of outcomes during the off-treatment period with outcomes during the open-label extension. “We used these boys as their own internal control, if you wish,” he said.
Creatine kinase levels decreased soon after treatment, as did other markers of muscle disease. The drug “seems to have an early and sustained biomarker response,” Dr. Finkel said.
Annualized rate of change on lower leg muscle MRI-T2 decreased. “There is a relative reduction and stabilization from week 12 all the way out through the open-label extension to 72 weeks,” he said. “It suggests that there is an early and sustained response in stabilization of the MRI as a biomarker.”
Timed function tests
A comparison of the annualized rates of change on timed function tests – including the 10-meter walk/run, time-to-stand, and four-stair-climb, and the North Star Ambulatory Assessment – during the off-treatment and on-treatment periods indicated slowing of disease progression with treatment. “Shortly after starting on drug ... there was a relative stabilization in each of these measures,” Dr. Finkel said.
In addition, the researchers observed an early signal of possible cardiac benefit. Mean heart rate at baseline was 99 bpm. On treatment, it decreased to 92 bpm. “Boys with DMD die typically of cardiomyopathy, so it is important to try to address the cardiac status,” he said.
The drug was safe and well tolerated. Most participants experienced mild gastrointestinal issues, which typically were transient. One serious adverse event during the trial occurred in a patient receiving placebo. Patients tended to have a stable body mass index during treatment, Dr. Finkel said.
During the open-label extension, patients had “clinically meaningful slowing of disease progression on edasalonexent,” relative to the off-treatment period, Dr. Finkel said. Investigators plan to further study edasalonexent for the treatment of DMD in a phase 3 trial. The phase 3 study, PolarisDMD, recently completed enrollment at 40 sites. Results could be available in about a year, Dr. Finkel said.
The study was sponsored by Catabasis. Dr. Finkel disclosed consulting work and grants or research support from Catabasis and other companies.
SOURCE: Finkel R et al. CNS 2019. Abstract PL1-3.
CHARLOTTE, N.C. – presented at the annual meeting of the Child Neurology Society.
The NF-kB pathway is “fundamental to the pathogenesis and biology of DMD,” said Richard Finkel, MD, chief of neurology at Nemours Children’s Health System in Orlando and principal investigator for the phase 2 study, known as MoveDMD.
A lack of dystrophin, combined with the mechanical stress of muscle contraction, activates the NF-kB pathway and inhibits muscle regeneration. “It is known that there is inflammation and fibrosis and release of cytokines early in life” in patients with DMD, Dr. Finkel said.
Independent of mutation
Edasalonexent is an NF-kB inhibitor that is being developed by Catabasis as a therapy for patients with DMD regardless of the genetic mutation that is causing the disease. It may be used as monotherapy or with other dystrophin-targeted treatments, Dr. Finkel said.
In a mouse model of DMD, an analog of the drug reduced muscle inflammation and increased the force of diaphragm muscle. To assess edasalonexent’s safety, pharmacokinetics, and effects on functional measures and MRI in patients with DMD, Dr. Finkel and colleagues conducted the MoveDMD trial. Investigators enrolled boys aged 4 years to younger than 8 years who were not receiving treatment with corticosteroids.
Researchers first examined drug safety and pharmacokinetics in 17 boys who received the treatment for 1 week. The investigators then followed 16 of these patients off treatment for as long as 6 months. This off-treatment period was followed by a phase 2, placebo-controlled period, during which the 16 patients and another 15 patients received edasalonexent 67 mg/kg/day, edasalonexent 100 mg/kg/day, or placebo for 12 weeks. Patients subsequently entered an open-label extension study.
Dr. Finkel presented a comparison of outcomes during the off-treatment period with outcomes during the open-label extension. “We used these boys as their own internal control, if you wish,” he said.
Creatine kinase levels decreased soon after treatment, as did other markers of muscle disease. The drug “seems to have an early and sustained biomarker response,” Dr. Finkel said.
Annualized rate of change on lower leg muscle MRI-T2 decreased. “There is a relative reduction and stabilization from week 12 all the way out through the open-label extension to 72 weeks,” he said. “It suggests that there is an early and sustained response in stabilization of the MRI as a biomarker.”
Timed function tests
A comparison of the annualized rates of change on timed function tests – including the 10-meter walk/run, time-to-stand, and four-stair-climb, and the North Star Ambulatory Assessment – during the off-treatment and on-treatment periods indicated slowing of disease progression with treatment. “Shortly after starting on drug ... there was a relative stabilization in each of these measures,” Dr. Finkel said.
In addition, the researchers observed an early signal of possible cardiac benefit. Mean heart rate at baseline was 99 bpm. On treatment, it decreased to 92 bpm. “Boys with DMD die typically of cardiomyopathy, so it is important to try to address the cardiac status,” he said.
The drug was safe and well tolerated. Most participants experienced mild gastrointestinal issues, which typically were transient. One serious adverse event during the trial occurred in a patient receiving placebo. Patients tended to have a stable body mass index during treatment, Dr. Finkel said.
During the open-label extension, patients had “clinically meaningful slowing of disease progression on edasalonexent,” relative to the off-treatment period, Dr. Finkel said. Investigators plan to further study edasalonexent for the treatment of DMD in a phase 3 trial. The phase 3 study, PolarisDMD, recently completed enrollment at 40 sites. Results could be available in about a year, Dr. Finkel said.
The study was sponsored by Catabasis. Dr. Finkel disclosed consulting work and grants or research support from Catabasis and other companies.
SOURCE: Finkel R et al. CNS 2019. Abstract PL1-3.
CHARLOTTE, N.C. – presented at the annual meeting of the Child Neurology Society.
The NF-kB pathway is “fundamental to the pathogenesis and biology of DMD,” said Richard Finkel, MD, chief of neurology at Nemours Children’s Health System in Orlando and principal investigator for the phase 2 study, known as MoveDMD.
A lack of dystrophin, combined with the mechanical stress of muscle contraction, activates the NF-kB pathway and inhibits muscle regeneration. “It is known that there is inflammation and fibrosis and release of cytokines early in life” in patients with DMD, Dr. Finkel said.
Independent of mutation
Edasalonexent is an NF-kB inhibitor that is being developed by Catabasis as a therapy for patients with DMD regardless of the genetic mutation that is causing the disease. It may be used as monotherapy or with other dystrophin-targeted treatments, Dr. Finkel said.
In a mouse model of DMD, an analog of the drug reduced muscle inflammation and increased the force of diaphragm muscle. To assess edasalonexent’s safety, pharmacokinetics, and effects on functional measures and MRI in patients with DMD, Dr. Finkel and colleagues conducted the MoveDMD trial. Investigators enrolled boys aged 4 years to younger than 8 years who were not receiving treatment with corticosteroids.
Researchers first examined drug safety and pharmacokinetics in 17 boys who received the treatment for 1 week. The investigators then followed 16 of these patients off treatment for as long as 6 months. This off-treatment period was followed by a phase 2, placebo-controlled period, during which the 16 patients and another 15 patients received edasalonexent 67 mg/kg/day, edasalonexent 100 mg/kg/day, or placebo for 12 weeks. Patients subsequently entered an open-label extension study.
Dr. Finkel presented a comparison of outcomes during the off-treatment period with outcomes during the open-label extension. “We used these boys as their own internal control, if you wish,” he said.
Creatine kinase levels decreased soon after treatment, as did other markers of muscle disease. The drug “seems to have an early and sustained biomarker response,” Dr. Finkel said.
Annualized rate of change on lower leg muscle MRI-T2 decreased. “There is a relative reduction and stabilization from week 12 all the way out through the open-label extension to 72 weeks,” he said. “It suggests that there is an early and sustained response in stabilization of the MRI as a biomarker.”
Timed function tests
A comparison of the annualized rates of change on timed function tests – including the 10-meter walk/run, time-to-stand, and four-stair-climb, and the North Star Ambulatory Assessment – during the off-treatment and on-treatment periods indicated slowing of disease progression with treatment. “Shortly after starting on drug ... there was a relative stabilization in each of these measures,” Dr. Finkel said.
In addition, the researchers observed an early signal of possible cardiac benefit. Mean heart rate at baseline was 99 bpm. On treatment, it decreased to 92 bpm. “Boys with DMD die typically of cardiomyopathy, so it is important to try to address the cardiac status,” he said.
The drug was safe and well tolerated. Most participants experienced mild gastrointestinal issues, which typically were transient. One serious adverse event during the trial occurred in a patient receiving placebo. Patients tended to have a stable body mass index during treatment, Dr. Finkel said.
During the open-label extension, patients had “clinically meaningful slowing of disease progression on edasalonexent,” relative to the off-treatment period, Dr. Finkel said. Investigators plan to further study edasalonexent for the treatment of DMD in a phase 3 trial. The phase 3 study, PolarisDMD, recently completed enrollment at 40 sites. Results could be available in about a year, Dr. Finkel said.
The study was sponsored by Catabasis. Dr. Finkel disclosed consulting work and grants or research support from Catabasis and other companies.
SOURCE: Finkel R et al. CNS 2019. Abstract PL1-3.
REPORTING FROM CNS 2019
Baricitinib may benefit patients with Aicardi-Goutières syndrome
CHARLOTTE, N.C. – Scores on a novel AGS scale improved, and skin and liver complications resolved in children with AGS who received treatment with baricitinib, according to results presented at the annual meeting of the Child Neurology Society.
AGS is caused by various heritable disorders of the innate immunity that result in excessive interferon production. AGS characteristically manifests as an early-onset encephalopathy that causes intellectual and physical disability, but patients may have a wide range of clinical phenotypes. The disease may involve the skin, liver, lungs, heart, and other organs, as well as the brain.
A multisystem disorder
“The neurologic features, while they are the most compelling for us, are really only the tip of the iceberg,” said Adeline Vanderver, MD, program director of the leukodystrophy center, and the Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at Children’s Hospital of Philadelphia. “Nearly every single organ system in the body is affected, from either direct interferon injury or from a secondary vasculopathy related to the interferonopathy.”
Dr. Vanderver presented results from the compassionate use study, which assessed whether the JAK inhibitor baricitinib (Olumiant) may decrease interferon signaling in AGS and limit the morbidity of the disease.
The phase 1, open-label trial “included compassionate use of baricitinib in AGS under the argument that these children did not have time to wait for approval of the drug,” said Dr. Vanderver. In 2018, the Food and Drug Administration approved baricitinib for moderate to severe rheumatoid arthritis in adults with an inadequate response to methotrexate.
The phase 1 trial in AGS included 35 patients with mutation-defined AGS and evidence of inflammatory disease that could be targeted by JAK inhibition. The trial population was 36% female. The average age of disease onset was 0.8 years, and patients’ average age at treatment was 6.1 years. The investigators assessed safety and laboratory data every 3 months and conducted clinical assessments every 6 months.
The heterogeneity of AGS phenotypes within families and across genotypes makes treatment trials in this disorder a challenge, Dr. Vanderver said. Outcome measures may have ceiling or floor effects that fail to capture the range of severity of AGS symptoms. Dr. Vanderver and colleagues developed a novel AGS scale to capture the scope of neurologic function in patients with AGS
.
When the researchers applied the AGS scale to a historical cohort of patients, most had stable scores about 6 months after disease onset. “After the first 6 months of the disease, the disease tends to be much more static, as the children have sustained significant neurologic injury,” Dr. Vanderver said.
They applied the novel AGS scale post hoc as an exploratory endpoint in the phase 1 trial. In addition, parents recorded information in a diary about skin involvement, irritability, seizures, and fever. “Over time, we see a reduction, although not always a statistically significant reduction, in symptom burden,” Dr. Vanderver said. The AGS clinical diary scores reflect “what the parents were telling us – that they felt like their children were feeling better during treatment,” she said.
Several patients had skin conditions that improved with treatment. One patient with dermatitis or eczema had the skin abnormality resolve within 3 days. A patient with full-body panniculitis began healing for the first time after about a month of treatment. Seasonal variations and dose adjustments led to fluctuations in some of the skin conditions. Nevertheless, the results suggested significant improvement in skin manifestations in patients with AGS, Dr. Vanderver said.
Patients generally had stable AGS scale scores in the year before treatment, although a couple of patients who were closer to disease onset had precipitous decline in neurologic function, she said. “We had a statistically significant increase in that scale of neurologic function in our patients during the period of the study, even in patients who had sometimes had years of disease duration,” said Dr. Vanderver.
Dr. Vanderver cautioned that she does not want to overstate the changes in function. Patients with AGS may have less potential for recuperation, compared with patients with other conditions. “A child with significant disruptive CNS disease may not recuperate normal functioning,” Dr. Vanderver said, “but it can be clinically meaningful to families if children start having better head control, smile, communicate, even if they might not regain all their motor milestones.”
In addition, a small subset of patients who had potentially life threatening liver complications from the disease experienced rapid normalization and improvement of liver function. “This blockade can be important not just for neurologic function but also to maintain normal physiologic homeostasis of other organs that are affected by the interferonopathy,” Dr. Vanderver said.
Interferon signaling scores decreased in the days after starting treatment and subsequently leveled out.
Serious adverse events that occurred during the trial, such as hospitalizations, were attributable to AGS. One child died from unrecognized pulmonary hypertension, which is now known to be a complication of AGS but was not at the time.
Harnessing a side effect
The most significant and recurrent laboratory abnormality was thrombocytosis. “That is a known complication of this family of drugs that in many cases allowed us to improve previous treatment-resistant thrombocytopenia, so we kind of like that side effect in most cases, but in two cases it did ... result in dose adjustments, although we never had to stop the medication for that.”
The study offers proof of principle that AGS is treatable, Dr. Vanderver said. A phase 2 trial is enrolling patients closer to disease onset. Early treatment of AGS may remain a challenge until there is newborn screening for the disease, she said.
Dr. Vanderver receives grant and in-kind support for translational research without personal compensation from Eli Lilly, Takeda, Illumina, Biogen, Homology, and Ionis. In addition, Dr. Vanderver serves on the scientific advisory boards of the European Leukodystrophy Association and the United Leukodystrophy Foundation, as well as in an unpaid capacity for Takeda, Ionis, Biogen, and Illumina.
Eli Lilly provided support for the phase 1 study. In addition, the study received support from the AGS Association Americas Family Foundation, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, and the Children’s Hospital of Philadelphia Research Institute.
SOURCE: Vanderver A et al. CNS 2019. Abstract PL1-6.
CHARLOTTE, N.C. – Scores on a novel AGS scale improved, and skin and liver complications resolved in children with AGS who received treatment with baricitinib, according to results presented at the annual meeting of the Child Neurology Society.
AGS is caused by various heritable disorders of the innate immunity that result in excessive interferon production. AGS characteristically manifests as an early-onset encephalopathy that causes intellectual and physical disability, but patients may have a wide range of clinical phenotypes. The disease may involve the skin, liver, lungs, heart, and other organs, as well as the brain.
A multisystem disorder
“The neurologic features, while they are the most compelling for us, are really only the tip of the iceberg,” said Adeline Vanderver, MD, program director of the leukodystrophy center, and the Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at Children’s Hospital of Philadelphia. “Nearly every single organ system in the body is affected, from either direct interferon injury or from a secondary vasculopathy related to the interferonopathy.”
Dr. Vanderver presented results from the compassionate use study, which assessed whether the JAK inhibitor baricitinib (Olumiant) may decrease interferon signaling in AGS and limit the morbidity of the disease.
The phase 1, open-label trial “included compassionate use of baricitinib in AGS under the argument that these children did not have time to wait for approval of the drug,” said Dr. Vanderver. In 2018, the Food and Drug Administration approved baricitinib for moderate to severe rheumatoid arthritis in adults with an inadequate response to methotrexate.
The phase 1 trial in AGS included 35 patients with mutation-defined AGS and evidence of inflammatory disease that could be targeted by JAK inhibition. The trial population was 36% female. The average age of disease onset was 0.8 years, and patients’ average age at treatment was 6.1 years. The investigators assessed safety and laboratory data every 3 months and conducted clinical assessments every 6 months.
The heterogeneity of AGS phenotypes within families and across genotypes makes treatment trials in this disorder a challenge, Dr. Vanderver said. Outcome measures may have ceiling or floor effects that fail to capture the range of severity of AGS symptoms. Dr. Vanderver and colleagues developed a novel AGS scale to capture the scope of neurologic function in patients with AGS
.
When the researchers applied the AGS scale to a historical cohort of patients, most had stable scores about 6 months after disease onset. “After the first 6 months of the disease, the disease tends to be much more static, as the children have sustained significant neurologic injury,” Dr. Vanderver said.
They applied the novel AGS scale post hoc as an exploratory endpoint in the phase 1 trial. In addition, parents recorded information in a diary about skin involvement, irritability, seizures, and fever. “Over time, we see a reduction, although not always a statistically significant reduction, in symptom burden,” Dr. Vanderver said. The AGS clinical diary scores reflect “what the parents were telling us – that they felt like their children were feeling better during treatment,” she said.
Several patients had skin conditions that improved with treatment. One patient with dermatitis or eczema had the skin abnormality resolve within 3 days. A patient with full-body panniculitis began healing for the first time after about a month of treatment. Seasonal variations and dose adjustments led to fluctuations in some of the skin conditions. Nevertheless, the results suggested significant improvement in skin manifestations in patients with AGS, Dr. Vanderver said.
Patients generally had stable AGS scale scores in the year before treatment, although a couple of patients who were closer to disease onset had precipitous decline in neurologic function, she said. “We had a statistically significant increase in that scale of neurologic function in our patients during the period of the study, even in patients who had sometimes had years of disease duration,” said Dr. Vanderver.
Dr. Vanderver cautioned that she does not want to overstate the changes in function. Patients with AGS may have less potential for recuperation, compared with patients with other conditions. “A child with significant disruptive CNS disease may not recuperate normal functioning,” Dr. Vanderver said, “but it can be clinically meaningful to families if children start having better head control, smile, communicate, even if they might not regain all their motor milestones.”
In addition, a small subset of patients who had potentially life threatening liver complications from the disease experienced rapid normalization and improvement of liver function. “This blockade can be important not just for neurologic function but also to maintain normal physiologic homeostasis of other organs that are affected by the interferonopathy,” Dr. Vanderver said.
Interferon signaling scores decreased in the days after starting treatment and subsequently leveled out.
Serious adverse events that occurred during the trial, such as hospitalizations, were attributable to AGS. One child died from unrecognized pulmonary hypertension, which is now known to be a complication of AGS but was not at the time.
Harnessing a side effect
The most significant and recurrent laboratory abnormality was thrombocytosis. “That is a known complication of this family of drugs that in many cases allowed us to improve previous treatment-resistant thrombocytopenia, so we kind of like that side effect in most cases, but in two cases it did ... result in dose adjustments, although we never had to stop the medication for that.”
The study offers proof of principle that AGS is treatable, Dr. Vanderver said. A phase 2 trial is enrolling patients closer to disease onset. Early treatment of AGS may remain a challenge until there is newborn screening for the disease, she said.
Dr. Vanderver receives grant and in-kind support for translational research without personal compensation from Eli Lilly, Takeda, Illumina, Biogen, Homology, and Ionis. In addition, Dr. Vanderver serves on the scientific advisory boards of the European Leukodystrophy Association and the United Leukodystrophy Foundation, as well as in an unpaid capacity for Takeda, Ionis, Biogen, and Illumina.
Eli Lilly provided support for the phase 1 study. In addition, the study received support from the AGS Association Americas Family Foundation, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, and the Children’s Hospital of Philadelphia Research Institute.
SOURCE: Vanderver A et al. CNS 2019. Abstract PL1-6.
CHARLOTTE, N.C. – Scores on a novel AGS scale improved, and skin and liver complications resolved in children with AGS who received treatment with baricitinib, according to results presented at the annual meeting of the Child Neurology Society.
AGS is caused by various heritable disorders of the innate immunity that result in excessive interferon production. AGS characteristically manifests as an early-onset encephalopathy that causes intellectual and physical disability, but patients may have a wide range of clinical phenotypes. The disease may involve the skin, liver, lungs, heart, and other organs, as well as the brain.
A multisystem disorder
“The neurologic features, while they are the most compelling for us, are really only the tip of the iceberg,” said Adeline Vanderver, MD, program director of the leukodystrophy center, and the Jacob A. Kamens Endowed Chair in Neurologic Disorders and Translational Neurotherapeutics at Children’s Hospital of Philadelphia. “Nearly every single organ system in the body is affected, from either direct interferon injury or from a secondary vasculopathy related to the interferonopathy.”
Dr. Vanderver presented results from the compassionate use study, which assessed whether the JAK inhibitor baricitinib (Olumiant) may decrease interferon signaling in AGS and limit the morbidity of the disease.
The phase 1, open-label trial “included compassionate use of baricitinib in AGS under the argument that these children did not have time to wait for approval of the drug,” said Dr. Vanderver. In 2018, the Food and Drug Administration approved baricitinib for moderate to severe rheumatoid arthritis in adults with an inadequate response to methotrexate.
The phase 1 trial in AGS included 35 patients with mutation-defined AGS and evidence of inflammatory disease that could be targeted by JAK inhibition. The trial population was 36% female. The average age of disease onset was 0.8 years, and patients’ average age at treatment was 6.1 years. The investigators assessed safety and laboratory data every 3 months and conducted clinical assessments every 6 months.
The heterogeneity of AGS phenotypes within families and across genotypes makes treatment trials in this disorder a challenge, Dr. Vanderver said. Outcome measures may have ceiling or floor effects that fail to capture the range of severity of AGS symptoms. Dr. Vanderver and colleagues developed a novel AGS scale to capture the scope of neurologic function in patients with AGS
.
When the researchers applied the AGS scale to a historical cohort of patients, most had stable scores about 6 months after disease onset. “After the first 6 months of the disease, the disease tends to be much more static, as the children have sustained significant neurologic injury,” Dr. Vanderver said.
They applied the novel AGS scale post hoc as an exploratory endpoint in the phase 1 trial. In addition, parents recorded information in a diary about skin involvement, irritability, seizures, and fever. “Over time, we see a reduction, although not always a statistically significant reduction, in symptom burden,” Dr. Vanderver said. The AGS clinical diary scores reflect “what the parents were telling us – that they felt like their children were feeling better during treatment,” she said.
Several patients had skin conditions that improved with treatment. One patient with dermatitis or eczema had the skin abnormality resolve within 3 days. A patient with full-body panniculitis began healing for the first time after about a month of treatment. Seasonal variations and dose adjustments led to fluctuations in some of the skin conditions. Nevertheless, the results suggested significant improvement in skin manifestations in patients with AGS, Dr. Vanderver said.
Patients generally had stable AGS scale scores in the year before treatment, although a couple of patients who were closer to disease onset had precipitous decline in neurologic function, she said. “We had a statistically significant increase in that scale of neurologic function in our patients during the period of the study, even in patients who had sometimes had years of disease duration,” said Dr. Vanderver.
Dr. Vanderver cautioned that she does not want to overstate the changes in function. Patients with AGS may have less potential for recuperation, compared with patients with other conditions. “A child with significant disruptive CNS disease may not recuperate normal functioning,” Dr. Vanderver said, “but it can be clinically meaningful to families if children start having better head control, smile, communicate, even if they might not regain all their motor milestones.”
In addition, a small subset of patients who had potentially life threatening liver complications from the disease experienced rapid normalization and improvement of liver function. “This blockade can be important not just for neurologic function but also to maintain normal physiologic homeostasis of other organs that are affected by the interferonopathy,” Dr. Vanderver said.
Interferon signaling scores decreased in the days after starting treatment and subsequently leveled out.
Serious adverse events that occurred during the trial, such as hospitalizations, were attributable to AGS. One child died from unrecognized pulmonary hypertension, which is now known to be a complication of AGS but was not at the time.
Harnessing a side effect
The most significant and recurrent laboratory abnormality was thrombocytosis. “That is a known complication of this family of drugs that in many cases allowed us to improve previous treatment-resistant thrombocytopenia, so we kind of like that side effect in most cases, but in two cases it did ... result in dose adjustments, although we never had to stop the medication for that.”
The study offers proof of principle that AGS is treatable, Dr. Vanderver said. A phase 2 trial is enrolling patients closer to disease onset. Early treatment of AGS may remain a challenge until there is newborn screening for the disease, she said.
Dr. Vanderver receives grant and in-kind support for translational research without personal compensation from Eli Lilly, Takeda, Illumina, Biogen, Homology, and Ionis. In addition, Dr. Vanderver serves on the scientific advisory boards of the European Leukodystrophy Association and the United Leukodystrophy Foundation, as well as in an unpaid capacity for Takeda, Ionis, Biogen, and Illumina.
Eli Lilly provided support for the phase 1 study. In addition, the study received support from the AGS Association Americas Family Foundation, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, and the Children’s Hospital of Philadelphia Research Institute.
SOURCE: Vanderver A et al. CNS 2019. Abstract PL1-6.
REPORTING FROM CNS 2019
Celiac disease may underlie seizures
CHARLOTTE, N.C. – , according to a retrospective chart review presented at the annual meeting of the Child Neurology Society. Associations between celiac disease and seizures may have implications for screening and treatment, said study author Shanna Swartwood, MD, a fellow in the department of pediatric neurology at University of Utah in Salt Lake City.
“Screening for [celiac disease] early in patients with epilepsy, specifically with temporal EEG findings and intractable epilepsy, is warranted given the improvement of seizure burden that may result from exclusion of gluten from the diet,” said Dr. Swartwood and colleagues.
About 10% of patients with celiac disease have clinical neurologic manifestations, such as seizures. To characterize features of epilepsy in a pediatric population with celiac disease and to examine the effect of a gluten-free diet on seizure burden, Dr. Swartwood and colleagues reviewed patients treated at Primary Children’s Hospital in Salt Lake City since 2002. They identified patients with ICD-10 codes for seizures or epilepsy and celiac disease and reviewed 187 charts in all.
In all, 40 patients with seizures had biopsy-proven celiac disease, and 22 had a diagnosis of celiac disease based on the presence of antibodies. Among those with biopsy-proven celiac disease, 43% had intractable seizures. Among those with antibody-positive celiac disease, 31% had intractable seizures.
Among patients with intractable epilepsy, seizure onset preceded the diagnosis of celiac disease by an average of 5 years. For patients with nonintractable epilepsy, the first seizure occurred 1 year before the celiac disease diagnosis on average, but some patients received a celiac disease diagnosis first.
Focal seizures with secondary generalization and generalized tonic clonic seizures were the most common seizure types in this cohort. Epileptiform activity most often was seen in the temporal lobe. While other studies in patients with celiac disease have found occipital epileptiform activity to be the most common, only one patient in this cohort had activity in that location, Dr. Swartwood noted.
Patients with intractable seizures who adhered to a gluten-free diet “had a fairly robust response in terms of seizure improvement,” she said. Seizure improvement, including a decrease in seizure frequency or a decrease in antiepileptic medication dosage, occurred in seven of nine patients in the biopsy-proven group and in two of three patients in the antibody-positive group who adhered to a gluten-free diet and had intractable seizures. One patient was able to stop antiepileptic medication, and one patient had a complete resolution of seizure activity.
The researchers plan to further study the relationship between celiac disease and epilepsy, including whether various HLA subtypes of celiac disease correlate with seizures, said coinvestigator Cristina Trandafir, MD, PhD, assistant professor of pediatric neurology at University of Utah.
The chart review included relatively few patients with limited data. Nevertheless, the results suggest that there may be “substantial lag time” from first seizure to celiac disease diagnosis and that “earlier diagnosis and earlier placement on a gluten-free diet may be beneficial,” Dr. Swartwood said. Celiac disease may be asymptomatic, and screening for celiac disease with a blood test may make sense for patients with intractable seizures, she said.
The researchers had no relevant disclosures.
CHARLOTTE, N.C. – , according to a retrospective chart review presented at the annual meeting of the Child Neurology Society. Associations between celiac disease and seizures may have implications for screening and treatment, said study author Shanna Swartwood, MD, a fellow in the department of pediatric neurology at University of Utah in Salt Lake City.
“Screening for [celiac disease] early in patients with epilepsy, specifically with temporal EEG findings and intractable epilepsy, is warranted given the improvement of seizure burden that may result from exclusion of gluten from the diet,” said Dr. Swartwood and colleagues.
About 10% of patients with celiac disease have clinical neurologic manifestations, such as seizures. To characterize features of epilepsy in a pediatric population with celiac disease and to examine the effect of a gluten-free diet on seizure burden, Dr. Swartwood and colleagues reviewed patients treated at Primary Children’s Hospital in Salt Lake City since 2002. They identified patients with ICD-10 codes for seizures or epilepsy and celiac disease and reviewed 187 charts in all.
In all, 40 patients with seizures had biopsy-proven celiac disease, and 22 had a diagnosis of celiac disease based on the presence of antibodies. Among those with biopsy-proven celiac disease, 43% had intractable seizures. Among those with antibody-positive celiac disease, 31% had intractable seizures.
Among patients with intractable epilepsy, seizure onset preceded the diagnosis of celiac disease by an average of 5 years. For patients with nonintractable epilepsy, the first seizure occurred 1 year before the celiac disease diagnosis on average, but some patients received a celiac disease diagnosis first.
Focal seizures with secondary generalization and generalized tonic clonic seizures were the most common seizure types in this cohort. Epileptiform activity most often was seen in the temporal lobe. While other studies in patients with celiac disease have found occipital epileptiform activity to be the most common, only one patient in this cohort had activity in that location, Dr. Swartwood noted.
Patients with intractable seizures who adhered to a gluten-free diet “had a fairly robust response in terms of seizure improvement,” she said. Seizure improvement, including a decrease in seizure frequency or a decrease in antiepileptic medication dosage, occurred in seven of nine patients in the biopsy-proven group and in two of three patients in the antibody-positive group who adhered to a gluten-free diet and had intractable seizures. One patient was able to stop antiepileptic medication, and one patient had a complete resolution of seizure activity.
The researchers plan to further study the relationship between celiac disease and epilepsy, including whether various HLA subtypes of celiac disease correlate with seizures, said coinvestigator Cristina Trandafir, MD, PhD, assistant professor of pediatric neurology at University of Utah.
The chart review included relatively few patients with limited data. Nevertheless, the results suggest that there may be “substantial lag time” from first seizure to celiac disease diagnosis and that “earlier diagnosis and earlier placement on a gluten-free diet may be beneficial,” Dr. Swartwood said. Celiac disease may be asymptomatic, and screening for celiac disease with a blood test may make sense for patients with intractable seizures, she said.
The researchers had no relevant disclosures.
CHARLOTTE, N.C. – , according to a retrospective chart review presented at the annual meeting of the Child Neurology Society. Associations between celiac disease and seizures may have implications for screening and treatment, said study author Shanna Swartwood, MD, a fellow in the department of pediatric neurology at University of Utah in Salt Lake City.
“Screening for [celiac disease] early in patients with epilepsy, specifically with temporal EEG findings and intractable epilepsy, is warranted given the improvement of seizure burden that may result from exclusion of gluten from the diet,” said Dr. Swartwood and colleagues.
About 10% of patients with celiac disease have clinical neurologic manifestations, such as seizures. To characterize features of epilepsy in a pediatric population with celiac disease and to examine the effect of a gluten-free diet on seizure burden, Dr. Swartwood and colleagues reviewed patients treated at Primary Children’s Hospital in Salt Lake City since 2002. They identified patients with ICD-10 codes for seizures or epilepsy and celiac disease and reviewed 187 charts in all.
In all, 40 patients with seizures had biopsy-proven celiac disease, and 22 had a diagnosis of celiac disease based on the presence of antibodies. Among those with biopsy-proven celiac disease, 43% had intractable seizures. Among those with antibody-positive celiac disease, 31% had intractable seizures.
Among patients with intractable epilepsy, seizure onset preceded the diagnosis of celiac disease by an average of 5 years. For patients with nonintractable epilepsy, the first seizure occurred 1 year before the celiac disease diagnosis on average, but some patients received a celiac disease diagnosis first.
Focal seizures with secondary generalization and generalized tonic clonic seizures were the most common seizure types in this cohort. Epileptiform activity most often was seen in the temporal lobe. While other studies in patients with celiac disease have found occipital epileptiform activity to be the most common, only one patient in this cohort had activity in that location, Dr. Swartwood noted.
Patients with intractable seizures who adhered to a gluten-free diet “had a fairly robust response in terms of seizure improvement,” she said. Seizure improvement, including a decrease in seizure frequency or a decrease in antiepileptic medication dosage, occurred in seven of nine patients in the biopsy-proven group and in two of three patients in the antibody-positive group who adhered to a gluten-free diet and had intractable seizures. One patient was able to stop antiepileptic medication, and one patient had a complete resolution of seizure activity.
The researchers plan to further study the relationship between celiac disease and epilepsy, including whether various HLA subtypes of celiac disease correlate with seizures, said coinvestigator Cristina Trandafir, MD, PhD, assistant professor of pediatric neurology at University of Utah.
The chart review included relatively few patients with limited data. Nevertheless, the results suggest that there may be “substantial lag time” from first seizure to celiac disease diagnosis and that “earlier diagnosis and earlier placement on a gluten-free diet may be beneficial,” Dr. Swartwood said. Celiac disease may be asymptomatic, and screening for celiac disease with a blood test may make sense for patients with intractable seizures, she said.
The researchers had no relevant disclosures.
REPORTING FROM CNS 2019
Pediatric epilepsy surgery may improve cognition and behavior
CHARLOTTE, NC – according to a study presented at the annual meeting of the Child Neurology Society. The presence of comorbidities such as mood disorders and autism may influence the likelihood of perceived improvement, whereas the type of surgery may not.
“The parents and the families of the patients perceive that, even if the patients are not completely seizure free, the behavior and cognitive outcomes are better if there is some sort of seizure improvement,” said Trishna Kantamneni, MD, director of pediatric epilepsy at UC Davis in Sacramento.
To assess behavioral and cognitive outcomes following pediatric epilepsy surgery and to identify factors that predict improvement, Dr. Kantamneni and colleagues at the Cleveland Clinic Epilepsy Center retrospectively reviewed 126 patients younger than 18 years who underwent epilepsy surgery for medically refractory epilepsy during 2009-2016.
The primary outcome measure was the Impact of Childhood Neurologic Disability Scale (ICNDS), a parent-reported scale that assesses the behavior, cognition, and physical or neurologic disability of children with epilepsy. Parents completed the ICNDS preoperatively and at 6, 12, and 24 months after surgery. The researchers constructed separate linear mixed effects models to identify predictors of postoperative changes in ICNDS score.
Of the 126 patients, 62.7% were male, the median duration of epilepsy was 4.7 years, and 69.8% were seizure-free at the 2-year follow-up. Postoperative ICNDS scores were available for 103 patients at 6 months and for 54 patients at 24 months.
Before surgery, the average total ICNDS score was 55.7. At 6 months after surgery, the average score was 34.6, and at 24 months, it was 32.1, representing significant improvement from baseline.
In addition, behavior, cognition, and epilepsy subscores also improved post operatively, and the improvement persisted through 24 months. ICNDS scores significantly improved “even in patients who were not seizure-free after surgery,” by an average of about 22 points, the researchers said.
The absence of comorbid autism, cognitive impairment, and global developmental impairment and the absence of anxiety, depression, and ADHD were predictors of improved total ICNDS scores. Tumor pathology and being seizure free at 2 years also predicted improved scores. Duration and type of epilepsy, the number of antiepileptic drugs that patients were taking before surgery, and lobe of surgery were not predictive of improved ICNDS scores.
Dr. Kantamneni had no relevant disclosures.
SOURCE: Kantamneni T et al. CNS 2019, Abstract 51.
CHARLOTTE, NC – according to a study presented at the annual meeting of the Child Neurology Society. The presence of comorbidities such as mood disorders and autism may influence the likelihood of perceived improvement, whereas the type of surgery may not.
“The parents and the families of the patients perceive that, even if the patients are not completely seizure free, the behavior and cognitive outcomes are better if there is some sort of seizure improvement,” said Trishna Kantamneni, MD, director of pediatric epilepsy at UC Davis in Sacramento.
To assess behavioral and cognitive outcomes following pediatric epilepsy surgery and to identify factors that predict improvement, Dr. Kantamneni and colleagues at the Cleveland Clinic Epilepsy Center retrospectively reviewed 126 patients younger than 18 years who underwent epilepsy surgery for medically refractory epilepsy during 2009-2016.
The primary outcome measure was the Impact of Childhood Neurologic Disability Scale (ICNDS), a parent-reported scale that assesses the behavior, cognition, and physical or neurologic disability of children with epilepsy. Parents completed the ICNDS preoperatively and at 6, 12, and 24 months after surgery. The researchers constructed separate linear mixed effects models to identify predictors of postoperative changes in ICNDS score.
Of the 126 patients, 62.7% were male, the median duration of epilepsy was 4.7 years, and 69.8% were seizure-free at the 2-year follow-up. Postoperative ICNDS scores were available for 103 patients at 6 months and for 54 patients at 24 months.
Before surgery, the average total ICNDS score was 55.7. At 6 months after surgery, the average score was 34.6, and at 24 months, it was 32.1, representing significant improvement from baseline.
In addition, behavior, cognition, and epilepsy subscores also improved post operatively, and the improvement persisted through 24 months. ICNDS scores significantly improved “even in patients who were not seizure-free after surgery,” by an average of about 22 points, the researchers said.
The absence of comorbid autism, cognitive impairment, and global developmental impairment and the absence of anxiety, depression, and ADHD were predictors of improved total ICNDS scores. Tumor pathology and being seizure free at 2 years also predicted improved scores. Duration and type of epilepsy, the number of antiepileptic drugs that patients were taking before surgery, and lobe of surgery were not predictive of improved ICNDS scores.
Dr. Kantamneni had no relevant disclosures.
SOURCE: Kantamneni T et al. CNS 2019, Abstract 51.
CHARLOTTE, NC – according to a study presented at the annual meeting of the Child Neurology Society. The presence of comorbidities such as mood disorders and autism may influence the likelihood of perceived improvement, whereas the type of surgery may not.
“The parents and the families of the patients perceive that, even if the patients are not completely seizure free, the behavior and cognitive outcomes are better if there is some sort of seizure improvement,” said Trishna Kantamneni, MD, director of pediatric epilepsy at UC Davis in Sacramento.
To assess behavioral and cognitive outcomes following pediatric epilepsy surgery and to identify factors that predict improvement, Dr. Kantamneni and colleagues at the Cleveland Clinic Epilepsy Center retrospectively reviewed 126 patients younger than 18 years who underwent epilepsy surgery for medically refractory epilepsy during 2009-2016.
The primary outcome measure was the Impact of Childhood Neurologic Disability Scale (ICNDS), a parent-reported scale that assesses the behavior, cognition, and physical or neurologic disability of children with epilepsy. Parents completed the ICNDS preoperatively and at 6, 12, and 24 months after surgery. The researchers constructed separate linear mixed effects models to identify predictors of postoperative changes in ICNDS score.
Of the 126 patients, 62.7% were male, the median duration of epilepsy was 4.7 years, and 69.8% were seizure-free at the 2-year follow-up. Postoperative ICNDS scores were available for 103 patients at 6 months and for 54 patients at 24 months.
Before surgery, the average total ICNDS score was 55.7. At 6 months after surgery, the average score was 34.6, and at 24 months, it was 32.1, representing significant improvement from baseline.
In addition, behavior, cognition, and epilepsy subscores also improved post operatively, and the improvement persisted through 24 months. ICNDS scores significantly improved “even in patients who were not seizure-free after surgery,” by an average of about 22 points, the researchers said.
The absence of comorbid autism, cognitive impairment, and global developmental impairment and the absence of anxiety, depression, and ADHD were predictors of improved total ICNDS scores. Tumor pathology and being seizure free at 2 years also predicted improved scores. Duration and type of epilepsy, the number of antiepileptic drugs that patients were taking before surgery, and lobe of surgery were not predictive of improved ICNDS scores.
Dr. Kantamneni had no relevant disclosures.
SOURCE: Kantamneni T et al. CNS 2019, Abstract 51.
REPORTING FROM CNS 2019
Delay in EEG monitoring associated with increased seizure duration in pediatric refractory status epilepticus
CHARLOTTE, NC – , according to a multicenter study that was presented at the annual meeting of the Child Neurology Society. Delays in initiating EEG monitoring are associated with longer seizure duration in this patient population.
Neurologists are advised to initiate continuous EEG monitoring rapidly for all cases of pediatric refractory status epilepticus. Little information is available, however, about patterns in the timing of EEG placement. In addition, the relationship between delays in the initiation of continuous EEG and outcomes of refractory status epilepticus are unknown. Dmitry Tchapyjnikov, MD, assistant professor of child neurology at Duke University in Durham, N.C., and colleagues evaluated trends in the time to continuous EEG initiation and examined whether delays are associated with longer seizure duration in children with refractory status epilepticus.
A retrospective analysis of pSERG data
Dr. Tchapyjnikov and colleagues analyzed data from 11 hospitals participating in the Pediatric Status Epilepticus Research Group (pSERG), a prospective, observational cohort. They focused on pediatric patients who were admitted from 2011 to 2017 with refractory status epilepticus, which they defined as a seizure that persisted after treatment with two or more antiseizure medications (ASMs), one of which had to be a nonbenzodiazepine ASM, or a continuous infusion. Eligible patients were between 1 month and 21 years old and had convulsive seizures at onset. Patients who had EEG placement before seizure onset were excluded.
The investigators included in their study 121 patients who had seizure durations of 3 or more hours. Based on an exploratory analysis of various time-point cutoffs, Dr. Tchapyjnikov and colleagues defined delayed continuous EEG placement as placement at more than 5 hours after seizure onset. They used the Kaplan–Meier estimator to assess time to continuous EEG and used covariate-adjusted proportional hazards models to examine the association between delay in continuous EEG placement and seizure duration.
EEG placement overall was delayed
The median time to continuous EEG placement after seizure onset was 9 hours. Approximately 4% of the children had continuous EEG placed within 1 hour, and 74% had it placed within 24 hours.
The investigators found that seizure onset outside the study hospital was associated with a higher likelihood of delayed time to EEG placement. “Females seemed to be more likely to have timely EEG placement,” said Dr. Tchapyjnikov. “I don’t have a physiological explanation for that.” The researchers saw no difference in treatment between patients who had timely EEG placement and those who had delayed EEG placement.
About 68% of children were having seizures at the time of continuous EEG placement. A presumed seizure etiology of CNS infection was associated with a higher likelihood of being in status epilepticus at the time of EEG placement. A history of epilepsy, developmental delay, or home ASM use, however, was associated with a lower likelihood of being in status epilepticus at time of EEG placement.
Dr. Tchapyjnikov’s group found that the 24-hour cumulative probability of seizure resolution was lower among patients who did not have continuous EEG initiation within 5 hours, compared with those who did (56% vs.70%). The association remained significant after the investigators adjusted the data for covariates that were independently associated with 24-hour seizure resolution (hazard ratio, 0.31).
The investigators included in their analysis patients who had seizure resolution before EEG placement, because restricting the analysis to patients who have persistent status epilepticus would have overemphasized the benefits of EEG, according to Dr. Tchapyjnikov. “Looking at the overall hazard ratios is a more conservative way of looking at these data.”
The study was not supported by external funding. Dr. Tchapyjnikov had no relevant disclosures.
CHARLOTTE, NC – , according to a multicenter study that was presented at the annual meeting of the Child Neurology Society. Delays in initiating EEG monitoring are associated with longer seizure duration in this patient population.
Neurologists are advised to initiate continuous EEG monitoring rapidly for all cases of pediatric refractory status epilepticus. Little information is available, however, about patterns in the timing of EEG placement. In addition, the relationship between delays in the initiation of continuous EEG and outcomes of refractory status epilepticus are unknown. Dmitry Tchapyjnikov, MD, assistant professor of child neurology at Duke University in Durham, N.C., and colleagues evaluated trends in the time to continuous EEG initiation and examined whether delays are associated with longer seizure duration in children with refractory status epilepticus.
A retrospective analysis of pSERG data
Dr. Tchapyjnikov and colleagues analyzed data from 11 hospitals participating in the Pediatric Status Epilepticus Research Group (pSERG), a prospective, observational cohort. They focused on pediatric patients who were admitted from 2011 to 2017 with refractory status epilepticus, which they defined as a seizure that persisted after treatment with two or more antiseizure medications (ASMs), one of which had to be a nonbenzodiazepine ASM, or a continuous infusion. Eligible patients were between 1 month and 21 years old and had convulsive seizures at onset. Patients who had EEG placement before seizure onset were excluded.
The investigators included in their study 121 patients who had seizure durations of 3 or more hours. Based on an exploratory analysis of various time-point cutoffs, Dr. Tchapyjnikov and colleagues defined delayed continuous EEG placement as placement at more than 5 hours after seizure onset. They used the Kaplan–Meier estimator to assess time to continuous EEG and used covariate-adjusted proportional hazards models to examine the association between delay in continuous EEG placement and seizure duration.
EEG placement overall was delayed
The median time to continuous EEG placement after seizure onset was 9 hours. Approximately 4% of the children had continuous EEG placed within 1 hour, and 74% had it placed within 24 hours.
The investigators found that seizure onset outside the study hospital was associated with a higher likelihood of delayed time to EEG placement. “Females seemed to be more likely to have timely EEG placement,” said Dr. Tchapyjnikov. “I don’t have a physiological explanation for that.” The researchers saw no difference in treatment between patients who had timely EEG placement and those who had delayed EEG placement.
About 68% of children were having seizures at the time of continuous EEG placement. A presumed seizure etiology of CNS infection was associated with a higher likelihood of being in status epilepticus at the time of EEG placement. A history of epilepsy, developmental delay, or home ASM use, however, was associated with a lower likelihood of being in status epilepticus at time of EEG placement.
Dr. Tchapyjnikov’s group found that the 24-hour cumulative probability of seizure resolution was lower among patients who did not have continuous EEG initiation within 5 hours, compared with those who did (56% vs.70%). The association remained significant after the investigators adjusted the data for covariates that were independently associated with 24-hour seizure resolution (hazard ratio, 0.31).
The investigators included in their analysis patients who had seizure resolution before EEG placement, because restricting the analysis to patients who have persistent status epilepticus would have overemphasized the benefits of EEG, according to Dr. Tchapyjnikov. “Looking at the overall hazard ratios is a more conservative way of looking at these data.”
The study was not supported by external funding. Dr. Tchapyjnikov had no relevant disclosures.
CHARLOTTE, NC – , according to a multicenter study that was presented at the annual meeting of the Child Neurology Society. Delays in initiating EEG monitoring are associated with longer seizure duration in this patient population.
Neurologists are advised to initiate continuous EEG monitoring rapidly for all cases of pediatric refractory status epilepticus. Little information is available, however, about patterns in the timing of EEG placement. In addition, the relationship between delays in the initiation of continuous EEG and outcomes of refractory status epilepticus are unknown. Dmitry Tchapyjnikov, MD, assistant professor of child neurology at Duke University in Durham, N.C., and colleagues evaluated trends in the time to continuous EEG initiation and examined whether delays are associated with longer seizure duration in children with refractory status epilepticus.
A retrospective analysis of pSERG data
Dr. Tchapyjnikov and colleagues analyzed data from 11 hospitals participating in the Pediatric Status Epilepticus Research Group (pSERG), a prospective, observational cohort. They focused on pediatric patients who were admitted from 2011 to 2017 with refractory status epilepticus, which they defined as a seizure that persisted after treatment with two or more antiseizure medications (ASMs), one of which had to be a nonbenzodiazepine ASM, or a continuous infusion. Eligible patients were between 1 month and 21 years old and had convulsive seizures at onset. Patients who had EEG placement before seizure onset were excluded.
The investigators included in their study 121 patients who had seizure durations of 3 or more hours. Based on an exploratory analysis of various time-point cutoffs, Dr. Tchapyjnikov and colleagues defined delayed continuous EEG placement as placement at more than 5 hours after seizure onset. They used the Kaplan–Meier estimator to assess time to continuous EEG and used covariate-adjusted proportional hazards models to examine the association between delay in continuous EEG placement and seizure duration.
EEG placement overall was delayed
The median time to continuous EEG placement after seizure onset was 9 hours. Approximately 4% of the children had continuous EEG placed within 1 hour, and 74% had it placed within 24 hours.
The investigators found that seizure onset outside the study hospital was associated with a higher likelihood of delayed time to EEG placement. “Females seemed to be more likely to have timely EEG placement,” said Dr. Tchapyjnikov. “I don’t have a physiological explanation for that.” The researchers saw no difference in treatment between patients who had timely EEG placement and those who had delayed EEG placement.
About 68% of children were having seizures at the time of continuous EEG placement. A presumed seizure etiology of CNS infection was associated with a higher likelihood of being in status epilepticus at the time of EEG placement. A history of epilepsy, developmental delay, or home ASM use, however, was associated with a lower likelihood of being in status epilepticus at time of EEG placement.
Dr. Tchapyjnikov’s group found that the 24-hour cumulative probability of seizure resolution was lower among patients who did not have continuous EEG initiation within 5 hours, compared with those who did (56% vs.70%). The association remained significant after the investigators adjusted the data for covariates that were independently associated with 24-hour seizure resolution (hazard ratio, 0.31).
The investigators included in their analysis patients who had seizure resolution before EEG placement, because restricting the analysis to patients who have persistent status epilepticus would have overemphasized the benefits of EEG, according to Dr. Tchapyjnikov. “Looking at the overall hazard ratios is a more conservative way of looking at these data.”
The study was not supported by external funding. Dr. Tchapyjnikov had no relevant disclosures.
REPORTING FROM CNS 2019