Alexandra K. Brooks, Vicente Quiroz, Luca Schierbaum, Julian E. Alecu, Katerina Bernardi, Nicole Battaglia, Amy Tam, Joshua Rong, Gregor Kasprian, Edward Yang, Darius Ebrahimi-Fakhari
Purpose
Adaptor protein complex 4–associated hereditary spastic paraplegia (AP-4-HSP) is a rare childhood-onset neurogenetic disorder. With gene replacement therapies advancing, early—potentially prenatal—diagnosis holds significant clinical promise. We aimed to characterize fetal and perinatal brain MRI features of AP-4-HSP to assess whether early imaging can prompt timely diagnosis, counseling, and interventions.
Methods
In this retrospective analysis, we reviewed prenatal imaging from 303 individuals with genetically confirmed AP-4-HSP enrolled in the Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (NCT04712812). Four patients (covering SPG47, SPG50, SPG52) with fetal, perinatal, or early postmortem imaging available were selected for detailed neuroradiologic evaluation. Systematic assessment documented several structural anomalies, correlated with genotype and clinical progression.
Results
Fetal imaging between 22 and 38 weeks' gestation revealed ventriculomegaly, corpus callosum hypoplasia, reduced periventricular white matter, and hippocampal under-rotation across all subtypes. The SPG52 patient exhibited additional severe features, including gyral immaturity and pontine/vermis hypoplasia. Postnatal follow-up demonstrated progressive white matter volume reduction and delayed myelination.
Conclusions
This study demonstrates that fetal and perinatal brain MRI can detect early, consistent neurodevelopmental abnormalities in AP-4-HSP, reinforcing its classification as both a neurodevelopmental and neurodegenerative disorder. Integration of prenatal neuroimaging with molecular diagnostics could enable earlier recognition, family counseling, and access to emerging gene therapies. These findings support the incorporation of fetal brain MRI into diagnostic protocols for suspected neurogenetic conditions.
{"title":"Fetal and Perinatal Brain MRI Findings in Adaptor Protein Complex 4–Associated Hereditary Spastic Paraplegia","authors":"Alexandra K. Brooks, Vicente Quiroz, Luca Schierbaum, Julian E. Alecu, Katerina Bernardi, Nicole Battaglia, Amy Tam, Joshua Rong, Gregor Kasprian, Edward Yang, Darius Ebrahimi-Fakhari","doi":"10.1002/cns3.70035","DOIUrl":"https://doi.org/10.1002/cns3.70035","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Adaptor protein complex 4–associated hereditary spastic paraplegia (AP-4-HSP) is a rare childhood-onset neurogenetic disorder. With gene replacement therapies advancing, early—potentially prenatal—diagnosis holds significant clinical promise. We aimed to characterize fetal and perinatal brain MRI features of AP-4-HSP to assess whether early imaging can prompt timely diagnosis, counseling, and interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this retrospective analysis, we reviewed prenatal imaging from 303 individuals with genetically confirmed AP-4-HSP enrolled in the Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (NCT04712812). Four patients (covering SPG47, SPG50, SPG52) with fetal, perinatal, or early postmortem imaging available were selected for detailed neuroradiologic evaluation. Systematic assessment documented several structural anomalies, correlated with genotype and clinical progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Fetal imaging between 22 and 38 weeks' gestation revealed ventriculomegaly, corpus callosum hypoplasia, reduced periventricular white matter, and hippocampal under-rotation across all subtypes. The SPG52 patient exhibited additional severe features, including gyral immaturity and pontine/vermis hypoplasia. Postnatal follow-up demonstrated progressive white matter volume reduction and delayed myelination.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>This study demonstrates that fetal and perinatal brain MRI can detect early, consistent neurodevelopmental abnormalities in AP-4-HSP, reinforcing its classification as both a neurodevelopmental and neurodegenerative disorder. Integration of prenatal neuroimaging with molecular diagnostics could enable earlier recognition, family counseling, and access to emerging gene therapies. These findings support the incorporation of fetal brain MRI into diagnostic protocols for suspected neurogenetic conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"226-231"},"PeriodicalIF":0.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Naomi Vos, Didem Demirbas, Lance Rodan, Edward Yang, Sanjay P. Prabhu, Jie Chen, Xiaoping Huang, Wanshu Qi, Robin L. Haynes, Maria K. Lehtinen, Michael J. Bennett, Miao He, Phillip L. Pearl, M. Estela Rubio-Gozalbo, Annapurna Poduri, Gerard T. Berry
Objective
The developmental and epileptic encephalopathies (DEE) are associated with serious and lifelong neurological conditions and risk of early mortality. Here, we describe the chronic treatment of a boy with PLCB1-related DEE with enteral myo-inositol supplementation as an add-on therapy to standard antiseizure medications that had been ineffective, and present novel findings in our lethal Slc5a3 knockout mouse model to substantiate our hypothesis for a novel role of myo-inositol in prenatal life.
Methods
Myo-inositol levels were measured in plasma, urine, and cerebrospinal fluid (CSF) using stable isotope dilution and selected ion monitoring gas chromatography/mass spectrometry. Brain function and structure were monitored with magnetic resonance spectroscopy, magnetic resonance imaging, and electroencephalograms. Safety studies were performed according to Food and Drug Administration requirements.
Results
Treatment was well tolerated without any adverse events. There was an improvement in seizure burden and stabilization of brain atrophy that was most evident in the first and second years of life. Myo-inositol administration to the pregnant Slc5a3 carrier mice increased the myo-inositol content in the CSF of the Slc5a3 knockout pups, which prevented their death.
Interpretation
High-dose enteral myo-inositol supplementation was safely used in a patient with epileptic encephalopathy due to PLCB1 deletion, increasing CSF levels and improving seizures and brain atrophy. The hypothesized mechanism involves restoring a fetal-like state with increased membrane potential, thereby reducing neuronal firing. Based on our experience, we encourage the exploration of high-dose myo-inositol in clinical trials involving infants with severe epileptic encephalopathy.
{"title":"The Use of Synaptic Extracellular Myo-Inositol to Treat Developmental and Epileptic Encephalopathy","authors":"E. Naomi Vos, Didem Demirbas, Lance Rodan, Edward Yang, Sanjay P. Prabhu, Jie Chen, Xiaoping Huang, Wanshu Qi, Robin L. Haynes, Maria K. Lehtinen, Michael J. Bennett, Miao He, Phillip L. Pearl, M. Estela Rubio-Gozalbo, Annapurna Poduri, Gerard T. Berry","doi":"10.1002/cns3.70029","DOIUrl":"10.1002/cns3.70029","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The developmental and epileptic encephalopathies (DEE) are associated with serious and lifelong neurological conditions and risk of early mortality. Here, we describe the chronic treatment of a boy with <i>PLCB1</i>-related DEE with enteral myo-inositol supplementation as an add-on therapy to standard antiseizure medications that had been ineffective, and present novel findings in our lethal <i>Slc5a3</i> knockout mouse model to substantiate our hypothesis for a novel role of myo-inositol in prenatal life.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Myo-inositol levels were measured in plasma, urine, and cerebrospinal fluid (CSF) using stable isotope dilution and selected ion monitoring gas chromatography/mass spectrometry. Brain function and structure were monitored with magnetic resonance spectroscopy, magnetic resonance imaging, and electroencephalograms. Safety studies were performed according to Food and Drug Administration requirements.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Treatment was well tolerated without any adverse events. There was an improvement in seizure burden and stabilization of brain atrophy that was most evident in the first and second years of life. Myo-inositol administration to the pregnant <i>Slc5a3</i> carrier mice increased the myo-inositol content in the CSF of the <i>Slc5a3</i> knockout pups, which prevented their death.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>High-dose enteral myo-inositol supplementation was safely used in a patient with epileptic encephalopathy due to <i>PLCB1</i> deletion, increasing CSF levels and improving seizures and brain atrophy. The hypothesized mechanism involves restoring a fetal-like state with increased membrane potential, thereby reducing neuronal firing. Based on our experience, we encourage the exploration of high-dose myo-inositol in clinical trials involving infants with severe epileptic encephalopathy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"201-207"},"PeriodicalIF":0.0,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12381637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christina A. Gurnett, Seth J. Perlman, Steven M. Rothman
<p>Arthur Prensky, who profoundly influenced two generations of pediatric neurologists, died on June 16, 2025, after a short illness. He was 94 and Professor Emeritus of Neurology at Washington University School of Medicine at the time of his death. His career spanned the evolution of pediatric neurology from a descriptive specialty to a field anchored in modern genetics and neuroscience.</p><p>After early childhood trauma, including some time in foster care, he attended the highly selective Bronx High School of Science and then graduated Phi Beta Kappa from Cornell. He went on to New York University Medical School and then came to Washington University and Barnes Hospital for medical internship and a 1-year research neurophysiology fellowship. This was followed by service in the Air Force School of Aviation Medicine, ironic since he was phobic of flying. He went on to neurology residency at the Massachusetts General Hospital and an additional 3 years of laboratory research focused on leukodystrophies.</p><p>In 1967 he “metamorphized” (his own word) into a child neurologist and returned to Washington University to direct a new division of pediatric neurology (Figure 1). In 1974 he was named the first Allen P. and Josephine B. Green Professor of Pediatric Neurology. He had wide-ranging interests and wrote on a variety of topics, including brain lipid metabolism and disorders of myelination; amino acidopathies; epilepsy; toxicity of antiseizure medications; peripheral neuropathies; and Sydenham's chorea. He had an exemplary approach to complicated patients—he tried to formulate as accurate a differential diagnosis as possible but at the end of this process inverted his thinking and asked: Could any treatable condition be present? In this way, he pulled out all stops to make sure his patients did not miss out on potential therapies. He emphasized this approach with residents.</p><p>In his later years he was especially interested in pediatric headache, with two of his former trainees becoming national authorities on this topic (Andrew Hershey and Kenneth Mack). With several Washington University colleagues, he coauthored books on nutrition and the brain, caring for children with handicaps, and neurological pathophysiology. His skills were recognized by awards and honors, including the Hower Award of the Child Neurology Society, presidency of the Child Neurology Society, and the Faculty Achievement Award of the Washington University Alumni Association.</p><p>Arthur's formal résumé, however, fails to capture the attributes and eccentricities that gained him such notoriety among child neurologists. He was more than six feet tall and, while physically imposing, was noticeably awkward. He frequently mentioned not only that he walked late but that he only learned to ride a bicycle at 12, with the latter milestone achieved because his success became a neighborhood project. This information was often shared with parents of his motor-delayed patients to give
从退休回到临床实践后，他还将大部分临床收入转移到一个基金，专门用于支持儿童神经内科住院医生的学习和旅行机会。亚瑟的两个妻子希拉·卡尔和薇薇安·阿德尔斯坦去世，他深爱着她们。在他们生命的最后时刻，当他们遇到困难的医疗问题时，他温柔地支持着他们。他的兄弟西蒙和一个侄子幸存下来。亚瑟还与前儿科神经学社会工作者卡罗尔·韦斯曼（Carol Weisman）和她已故的丈夫弗兰克·罗宾斯（Frank Robbins）有着半个世纪的深厚友谊。传统的说法是：“亚瑟王的去世标志着一个时代的结束。”但这是一种曲解。从很多方面来说，亚瑟的时代结束于20世纪80年代，他在学术上的伟大之处在于他认识到了这个不断变化的环境。他看到神经学正迅速变得越来越科学，他尽其所能鼓励他的同事和住院医生参与这个新世界。他自己更喜欢病人的持续参与，并使自己能够在临床工作中支持其他需要帮助的人，甚至在2000年退休后再次为病人看病（图4）。我们将用最先进的现代科学技术来治疗我们的每一位病人，以此向他致敬。Christina A. Gurnett：概念化；写作——原稿；写作——审阅和编辑。Seth J. Perlman：概念化；写作——原稿；写作——审阅和编辑。Steven M. Rothman：概念化；写作——原稿；写作——审阅和编辑。
{"title":"Arthur L. Prensky, 1930–2025","authors":"Christina A. Gurnett, Seth J. Perlman, Steven M. Rothman","doi":"10.1002/cns3.70034","DOIUrl":"https://doi.org/10.1002/cns3.70034","url":null,"abstract":"<p>Arthur Prensky, who profoundly influenced two generations of pediatric neurologists, died on June 16, 2025, after a short illness. He was 94 and Professor Emeritus of Neurology at Washington University School of Medicine at the time of his death. His career spanned the evolution of pediatric neurology from a descriptive specialty to a field anchored in modern genetics and neuroscience.</p><p>After early childhood trauma, including some time in foster care, he attended the highly selective Bronx High School of Science and then graduated Phi Beta Kappa from Cornell. He went on to New York University Medical School and then came to Washington University and Barnes Hospital for medical internship and a 1-year research neurophysiology fellowship. This was followed by service in the Air Force School of Aviation Medicine, ironic since he was phobic of flying. He went on to neurology residency at the Massachusetts General Hospital and an additional 3 years of laboratory research focused on leukodystrophies.</p><p>In 1967 he “metamorphized” (his own word) into a child neurologist and returned to Washington University to direct a new division of pediatric neurology (Figure 1). In 1974 he was named the first Allen P. and Josephine B. Green Professor of Pediatric Neurology. He had wide-ranging interests and wrote on a variety of topics, including brain lipid metabolism and disorders of myelination; amino acidopathies; epilepsy; toxicity of antiseizure medications; peripheral neuropathies; and Sydenham's chorea. He had an exemplary approach to complicated patients—he tried to formulate as accurate a differential diagnosis as possible but at the end of this process inverted his thinking and asked: Could any treatable condition be present? In this way, he pulled out all stops to make sure his patients did not miss out on potential therapies. He emphasized this approach with residents.</p><p>In his later years he was especially interested in pediatric headache, with two of his former trainees becoming national authorities on this topic (Andrew Hershey and Kenneth Mack). With several Washington University colleagues, he coauthored books on nutrition and the brain, caring for children with handicaps, and neurological pathophysiology. His skills were recognized by awards and honors, including the Hower Award of the Child Neurology Society, presidency of the Child Neurology Society, and the Faculty Achievement Award of the Washington University Alumni Association.</p><p>Arthur's formal résumé, however, fails to capture the attributes and eccentricities that gained him such notoriety among child neurologists. He was more than six feet tall and, while physically imposing, was noticeably awkward. He frequently mentioned not only that he walked late but that he only learned to ride a bicycle at 12, with the latter milestone achieved because his success became a neighborhood project. This information was often shared with parents of his motor-delayed patients to give ","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"132-134"},"PeriodicalIF":0.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Siefaddeen Sharayah, Jennifer Griffith, Brad W. Warner, Liu Lin Thio
The ketogenic diet (KD) is a high-fat, low-carbohydrate, adequate-protein diet used for a century to treat drug-resistant epilepsy. It has relatively mild adverse effects. We highlight a patient who developed severe gastrointestinal (GI) symptoms related to a chylolymphatic mesenteric cyst (CMC) after KD initiation.
This boy was born at 39 weeks weighing 3490 g after an uneventful term gestation. Growth and development were initially appropriate. At 6 months of age he developed seizures manifested by episodes of right head-turning, rightward gaze deviation, impaired responsiveness, sometimes with chewing movements, decreased tone on the left, and/or shaking of the right extremities. These episodes had an ictal electrographic correlate with a diffuse onset but better evolution on the right on continuous video electroencephalography (EEG). Interictally, EEG showed epileptiform discharges in multiple areas on the right, resulting in a diagnosis of focal seizures with impaired consciousness. An epilepsy gene panel identified a heterozygous, paternally inherited, autosomal recessive, pathogenic variant in the biotinidase gene (BTD) (c.1368A>C, p.Q456H). A chromosomal microarray showed a maternally inherited, 329 kb duplication within 11p14.3 (arr[GRCh37]11p14.3(21897259_22226105)x3 mat). Brain magnetic resonance imaging was normal.
Levetiracetam, zonisamide, and clobazam failed to control seizures. Biotin therapy was not trialed. Oxcarbazepine reduced seizures but was limited by diarrhea and poor sleep. At 22 months, he began a 3:1 KD but was discharged on 2:1 due to acidosis and hypoglycemia. His abdominal examination was unremarkable. His seizure burden decreased from two to four seizures per day to a few times per week within the first 3 months, during which his KD ratio was gradually increased to 2.75:1.
Three months after starting the KD, he experienced intermittent severe abdominal pain, vomiting, and diarrhea for 5 days. An abdominal computed tomography scan revealed a predominantly hypoattenuating soft tissue mass measuring 35 × 43 × 41 mm arising from the root of the mesentery, causing mass effect on small bowel loops and abutting on branches of the superior mesenteric vein and artery with mesenteric lymphadenopathy (Figure 1). He underwent exploratory laparotomy with resection of a 5 cm chylous-appearing cystic mass in the mesenteric root, along with an 11 cm segment of adjacent small bowel, followed by re-anastomosis (Figure 2). Postoperatively, symptoms resolved, and tolerance to a 2.75:1 KD improved. His last seizures occurred immediately after surgery. He was weaned off oxcarbazepine 10 months after diet initiation, and he was weaned off the diet 2 years after surgery. Now 7 years of age, he remains seizure-free with near-normal development and no cyst recurrence. He has had three normal EEGs, including one overnight on the diet and one after diet discontinuation.
{"title":"Chylolymphatic Mesenteric Cyst as a Possible Ketogenic Diet Complication","authors":"Siefaddeen Sharayah, Jennifer Griffith, Brad W. Warner, Liu Lin Thio","doi":"10.1002/cns3.70028","DOIUrl":"https://doi.org/10.1002/cns3.70028","url":null,"abstract":"<p>The ketogenic diet (KD) is a high-fat, low-carbohydrate, adequate-protein diet used for a century to treat drug-resistant epilepsy. It has relatively mild adverse effects. We highlight a patient who developed severe gastrointestinal (GI) symptoms related to a chylolymphatic mesenteric cyst (CMC) after KD initiation.</p><p>This boy was born at 39 weeks weighing 3490 g after an uneventful term gestation. Growth and development were initially appropriate. At 6 months of age he developed seizures manifested by episodes of right head-turning, rightward gaze deviation, impaired responsiveness, sometimes with chewing movements, decreased tone on the left, and/or shaking of the right extremities. These episodes had an ictal electrographic correlate with a diffuse onset but better evolution on the right on continuous video electroencephalography (EEG). Interictally, EEG showed epileptiform discharges in multiple areas on the right, resulting in a diagnosis of focal seizures with impaired consciousness. An epilepsy gene panel identified a heterozygous, paternally inherited, autosomal recessive, pathogenic variant in the biotinidase gene (<i>BTD</i>) (c.1368A>C, p.Q456H). A chromosomal microarray showed a maternally inherited, 329 kb duplication within 11p14.3 (arr[GRCh37]11p14.3(21897259_22226105)x3 mat). Brain magnetic resonance imaging was normal.</p><p>Levetiracetam, zonisamide, and clobazam failed to control seizures. Biotin therapy was not trialed. Oxcarbazepine reduced seizures but was limited by diarrhea and poor sleep. At 22 months, he began a 3:1 KD but was discharged on 2:1 due to acidosis and hypoglycemia. His abdominal examination was unremarkable. His seizure burden decreased from two to four seizures per day to a few times per week within the first 3 months, during which his KD ratio was gradually increased to 2.75:1.</p><p>Three months after starting the KD, he experienced intermittent severe abdominal pain, vomiting, and diarrhea for 5 days. An abdominal computed tomography scan revealed a predominantly hypoattenuating soft tissue mass measuring 35 × 43 × 41 mm arising from the root of the mesentery, causing mass effect on small bowel loops and abutting on branches of the superior mesenteric vein and artery with mesenteric lymphadenopathy (Figure 1). He underwent exploratory laparotomy with resection of a 5 cm chylous-appearing cystic mass in the mesenteric root, along with an 11 cm segment of adjacent small bowel, followed by re-anastomosis (Figure 2). Postoperatively, symptoms resolved, and tolerance to a 2.75:1 KD improved. His last seizures occurred immediately after surgery. He was weaned off oxcarbazepine 10 months after diet initiation, and he was weaned off the diet 2 years after surgery. Now 7 years of age, he remains seizure-free with near-normal development and no cyst recurrence. He has had three normal EEGs, including one overnight on the diet and one after diet discontinuation.</p><p>We classified the abdominal mass in o","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"240-241"},"PeriodicalIF":0.0,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70028","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The objective of this study was to examine the correctness of the statement that the diagnosis of shaken baby syndrome (SBS) is a “medical conclusion.”
Design
If the outcome of an event is considered bad, people tend to attribute intent or responsibility. Against this backdrop, a randomized, blinded trial was applied using two case-based questionnaires of possible violent shaking of an infant, identical except for the outcome: fatal or nonfatal.
Setting
We used a report of a 2-month-old baby who had suddenly stopped breathing and was subsequently shaken by the father with the intention to resuscitate him. After admission, encephalopathy, subdural hemorrhages, and retinal hemorrhages were detected.
Participants
A total of 1269 randomly selected physicians received the questionnaire, whose distribution was randomized and blinded. The participants were not informed about the existence of two versions of the questionnaire.
Results
The participants who responded to the fatal version considered in a significantly higher proportion (79% [95% CI: 73−85]) that shaking caused the triad findings than those who responded to the nonfatal version (68% [95% CI: 61−75]) (p = 0.01). When pediatricians and ophthalmologists are merged, the corresponding proportions were (91% [95% CI: 86−96]) versus (74% [95% CI: 66−82]) (p = 0.001). Radiologists and forensic pathologists did not distinguish significantly between fatal and nonfatal outcomes.
Conclusion
The study indicates that among pediatricians and ophthalmologists, the diagnostic process in suspected SBS is more value-based than evidence-based. As these two specialties dominate the SBS diagnostic procedure, the SBS diagnosis is, in this sense, not strictly a “medical conclusion.”
{"title":"Questionnaire-Based Experimental Study of the Diagnostic Process in Suspected Shaken Baby Syndrome","authors":"N. Lynøe, A. Castor, N. Juth, A. Eriksson","doi":"10.1002/cns3.70031","DOIUrl":"https://doi.org/10.1002/cns3.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to examine the correctness of the statement that the diagnosis of shaken baby syndrome (SBS) is a “medical conclusion.”</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Design</h3>\u0000 \u0000 <p>If the outcome of an event is considered bad, people tend to attribute intent or responsibility. Against this backdrop, a randomized, blinded trial was applied using two case-based questionnaires of possible violent shaking of an infant, identical except for the outcome: fatal or nonfatal.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Setting</h3>\u0000 \u0000 <p>We used a report of a 2-month-old baby who had suddenly stopped breathing and was subsequently shaken by the father with the intention to resuscitate him. After admission, encephalopathy, subdural hemorrhages, and retinal hemorrhages were detected.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Participants</h3>\u0000 \u0000 <p>A total of 1269 randomly selected physicians received the questionnaire, whose distribution was randomized and blinded. The participants were not informed about the existence of two versions of the questionnaire.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The participants who responded to the fatal version considered in a significantly higher proportion (79% [95% CI: 73−85]) that shaking caused the triad findings than those who responded to the nonfatal version (68% [95% CI: 61−75]) (<i>p</i> = 0.01). When pediatricians and ophthalmologists are merged, the corresponding proportions were (91% [95% CI: 86−96]) versus (74% [95% CI: 66−82]) (<i>p</i> = 0.001). Radiologists and forensic pathologists did not distinguish significantly between fatal and nonfatal outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The study indicates that among pediatricians and ophthalmologists, the diagnostic process in suspected SBS is more value-based than evidence-based. As these two specialties dominate the SBS diagnostic procedure, the SBS diagnosis is, in this sense, not strictly a “medical conclusion.”</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"158-164"},"PeriodicalIF":0.0,"publicationDate":"2025-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mahesh Chikkannaiah, Sarah G. Yu, Laura D. Fonseca, Ajay Goenka, Gogi Kumar
<p>In countries where tuberculosis (TB) is endemic, children with tuberculous meningitis (TBM) commonly present with cerebrovascular complications such as stroke [<span>1</span>]. Herein, we present a patient from the United States with stroke associated with focal cerebral arteriopathy (FCA) secondary to TBM.</p><p>This 11-month-old girl presented with left hemiparesis and seizure. About 1.5 weeks before presentation, her parents noticed fatigue and decreased appetite and that she was not crawling as usual. Two days before presentation, her parents noticed decreased strength in her left arm and leg. Computed tomography of the head showed an area of hypoattenuation in the right basal ganglia and loss of gray and white matter differentiation in the right frontal cortex. While en route to our hospital, she had a seizure described as bilateral upper extremity shaking lasting 1 min, which self-resolved. On examination, she had right preferential gaze and left hemiparesis. Laboratory findings were significant for hyponatremia of 126 mEq/L. Magnetic resonance imaging of the brain (Figure 1) showed a right middle cerebral artery (MCA) distribution ischemic stroke. Magnetic resonance angiography (Figure 2) showed decreased flow in the right supraclinoid portion of the right internal carotid artery (ICA), A1 segment of the right anterior cerebral artery (ACA), and M1 segment of the right MCA and mild narrowing involving the petrous portion of the right carotid artery and carotid siphon. Her evaluation included cerebrospinal fluid (CSF) evaluation, which showed pleocytosis (235 cells/μL) with hypoglycorrhachia (11 mg/dL) and an elevated CSF protein (272 mg/dL).</p><p>Additional evaluation included CSF testing (bacterial culture, viral meningitis/encephalitis panel, herpes simplex virus polymerase chain reaction [PCR], and varicella virus PCR and antibodies) and respiratory panel for COVID-19, which were all negative. Chest computed tomography showed mediastinal and right hilar lymphadenopathy as well as nodular opacities in bilateral upper lobes with a miliary pattern.</p><p>Further family history included exposure to grandfather 1 month before his diagnosis of active TB; her grandfather had recently traveled to his native country, where TB is endemic. An interferon-gamma release assay and gastric aspirate culture were positive for <i>Mycobacterium tuberculosis</i>. The TB skin test was also positive. A CSF acid-fast bacilli culture was negative. She was diagnosed with FCA with right MCA stroke secondary to TBM and disseminated TB. She was treated with steroids and antitubercular therapy. Her seizures were controlled with levetiracetam and phenobarbital, which were weaned off as an outpatient. Upon the most recent follow-up at 3 years of age, she had spastic left hemiplegia, and she was able to sit independently but was not walking yet.</p><p>TB affects 1.2 million children worldwide, with an estimated 4% of TB diagnoses progressing to TBM [<span>1-3</span
在结核病流行的国家，患有结核性脑膜炎（TBM）的儿童通常伴有脑血管并发症，如脑卒中。在此，我们报告了一位来自美国的脑卒中伴局灶性脑动脉病变（FCA）继发于TBM的患者。这个11个月大的女孩表现为左偏瘫和癫痫。大约在分娩前1.5周，她的父母注意到她的疲劳和食欲下降，并且她不像往常那样爬行。在就诊前两天，她的父母注意到她左臂和左腿的力量有所下降。头部计算机断层扫描显示右侧基底节区低衰减，右侧额叶皮层灰质和白质分化丧失。在去我们医院的途中，她癫痫发作，描述为双侧上肢颤抖，持续1分钟，并自行消退。经检查，患者有右倾凝视和左偏瘫。实验室结果对126 mEq/L的低钠血症有显著意义。脑磁共振成像（图1）显示右脑中动脉（MCA）分布缺血性卒中。磁共振血管造影（图2）显示右侧颈内动脉（ICA）、右侧大脑前动脉（ACA） A1段和右侧MCA M1段血流减少，轻度狭窄累及右侧颈动脉岩部和颈动脉虹吸。脑脊液（CSF）检查显示细胞增多（235个细胞/μL），低糖血症（11 mg/dL）和脑脊液蛋白升高（272 mg/dL）。其他评估包括脑脊液检测（细菌培养、病毒性脑膜炎/脑炎面板、单纯疱疹病毒聚合酶链反应[PCR]、水痘病毒聚合酶链反应和抗体）和COVID-19呼吸道面板，均为阴性。胸部电脑断层显示纵隔及右侧肺门淋巴结病变及双侧上叶结节性混浊，呈军事征状。进一步的家族史包括在祖父诊断出活动性结核病前1个月与祖父接触；她的祖父最近回到了肺结核流行的祖国。干扰素释放试验和胃抽吸培养均为结核分枝杆菌阳性。结核菌皮肤试验也呈阳性。脑脊液抗酸杆菌培养阴性。她被诊断为FCA，右MCA中风继发于TBM和播散性结核病。她接受了类固醇和抗结核治疗。她的癫痫发作由左乙拉西坦和苯巴比妥控制，这两种药物在门诊时停用。在3岁时的最近一次随访中，她患有痉挛性左偏瘫，她能够独立坐着，但还不能走路。结核病影响全世界120万儿童，估计有4%的结核病诊断进展为结核性结核[1-3]。TBM在儿童中的发病率高峰为2-4岁，表现从发热、头痛等非特异性症状到更进行性的症状，包括脑神经麻痹、局灶性神经功能缺损和中风[1,3,4]。在VIPS研究中，与近端MCA受累与其他病因相关的FCA相比，远端ICA通常累及感染相关的FCA（如脑膜炎），就像我们的患者一样。尽管累及MCA和ACA并不罕见，但累及远端ICA的FCA应考虑感染。在我们的患者中，影像学结果怀疑是感染相关的FCA，这促使我们进行了评估。低钠血症、脑脊液检查结果以及与患有结核病的祖父接触史指导了我们对该患者的诊断。我们的病人强调了感染相关FCA的影像学特征。随着国际旅行和全球移民的增加，即使是非流行国家的临床医生也应在其鉴别诊断中考虑结核病。Mahesh Chikkannaiah：概念化，调查，写作-原稿，写作-审查和编辑，方法论，可视化，监督。Sarah G. Yu：调查，写作-原稿，写作-审查和编辑。劳拉·d·丰塞卡：写作-原稿，写作-审查和编辑，项目管理。阿杰伊·葛印卡：写作——评论和编辑。高基库马尔：写作-审查和编辑，监督。从患者的法定监护人处获得了一份同意披露表格，授权发布本文中包含的信息。该病例报告得到了医院机构审查委员会的认可（研究#2023-003，IRB# 2002722），并被确定为非研究活动。作者声明无利益冲突。
{"title":"Focal Cerebral Arteriopathy and Stroke Secondary to Tuberculous Meningitis","authors":"Mahesh Chikkannaiah, Sarah G. Yu, Laura D. Fonseca, Ajay Goenka, Gogi Kumar","doi":"10.1002/cns3.70032","DOIUrl":"https://doi.org/10.1002/cns3.70032","url":null,"abstract":"<p>In countries where tuberculosis (TB) is endemic, children with tuberculous meningitis (TBM) commonly present with cerebrovascular complications such as stroke [<span>1</span>]. Herein, we present a patient from the United States with stroke associated with focal cerebral arteriopathy (FCA) secondary to TBM.</p><p>This 11-month-old girl presented with left hemiparesis and seizure. About 1.5 weeks before presentation, her parents noticed fatigue and decreased appetite and that she was not crawling as usual. Two days before presentation, her parents noticed decreased strength in her left arm and leg. Computed tomography of the head showed an area of hypoattenuation in the right basal ganglia and loss of gray and white matter differentiation in the right frontal cortex. While en route to our hospital, she had a seizure described as bilateral upper extremity shaking lasting 1 min, which self-resolved. On examination, she had right preferential gaze and left hemiparesis. Laboratory findings were significant for hyponatremia of 126 mEq/L. Magnetic resonance imaging of the brain (Figure 1) showed a right middle cerebral artery (MCA) distribution ischemic stroke. Magnetic resonance angiography (Figure 2) showed decreased flow in the right supraclinoid portion of the right internal carotid artery (ICA), A1 segment of the right anterior cerebral artery (ACA), and M1 segment of the right MCA and mild narrowing involving the petrous portion of the right carotid artery and carotid siphon. Her evaluation included cerebrospinal fluid (CSF) evaluation, which showed pleocytosis (235 cells/μL) with hypoglycorrhachia (11 mg/dL) and an elevated CSF protein (272 mg/dL).</p><p>Additional evaluation included CSF testing (bacterial culture, viral meningitis/encephalitis panel, herpes simplex virus polymerase chain reaction [PCR], and varicella virus PCR and antibodies) and respiratory panel for COVID-19, which were all negative. Chest computed tomography showed mediastinal and right hilar lymphadenopathy as well as nodular opacities in bilateral upper lobes with a miliary pattern.</p><p>Further family history included exposure to grandfather 1 month before his diagnosis of active TB; her grandfather had recently traveled to his native country, where TB is endemic. An interferon-gamma release assay and gastric aspirate culture were positive for <i>Mycobacterium tuberculosis</i>. The TB skin test was also positive. A CSF acid-fast bacilli culture was negative. She was diagnosed with FCA with right MCA stroke secondary to TBM and disseminated TB. She was treated with steroids and antitubercular therapy. Her seizures were controlled with levetiracetam and phenobarbital, which were weaned off as an outpatient. Upon the most recent follow-up at 3 years of age, she had spastic left hemiplegia, and she was able to sit independently but was not walking yet.</p><p>TB affects 1.2 million children worldwide, with an estimated 4% of TB diagnoses progressing to TBM [<span>1-3</span","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"242-244"},"PeriodicalIF":0.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70032","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145100995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ruba Al-Ramadhani, Ann Hyslop, Avery R. Caraway, Edward J. Novotny, Adam P. Ostendorf, Krista L. Eschbach, Allyson L. Alexander, Lily C. Wong-Kisiel, Dewi F. Depositario-Cabacar, Chima O. Oluigbo, Cemal Karakas, Samir R. Karia, Priyamvada Tatachar, Jeffrey Bolton, Pilar D. Pichon, Daniel W. Shrey, Erin Fedak Romanowski, Nancy A. McNamara, Ernesto Gonzalez-Giraldo, Kurtis Auguste, Danilo Bernardo, Rani K. Singh, Pradeep K. Javarayee, Jenny J. Lin, Jason C. Coryell, Shilpa B. Reddy, Abhinaya Ganesh, Michael A. Ciliberto, Debopam Samanta, Kristen H. Arredondo, Ahmad Marashly, Zachary M. Grinspan, Dallas Armstrong, Taylor J. Abel, Janelle Wagner, Derryl J. Miller, Fernando N. Galan, Michael Scott Perry
<div> <section> <h3> Rationale</h3> <p>Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays.</p> </section> <section> <h3> Methods</h3> <p>We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug-resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra- and inter-institution variability and to delineate institutions with the shortest added duration for each variable.</p> </section> <section> <h3> Results</h3> <p>Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short-duration evaluations and 414 (25%) were long-duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups.</p> </section> <section> <h3> Conclusions</h3> <p>Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commo
{"title":"Factors Influencing the Duration From the Initiation of Surgical Evaluation to Final Intervention in Pediatric Epilepsy Surgery","authors":"Ruba Al-Ramadhani, Ann Hyslop, Avery R. Caraway, Edward J. Novotny, Adam P. Ostendorf, Krista L. Eschbach, Allyson L. Alexander, Lily C. Wong-Kisiel, Dewi F. Depositario-Cabacar, Chima O. Oluigbo, Cemal Karakas, Samir R. Karia, Priyamvada Tatachar, Jeffrey Bolton, Pilar D. Pichon, Daniel W. Shrey, Erin Fedak Romanowski, Nancy A. McNamara, Ernesto Gonzalez-Giraldo, Kurtis Auguste, Danilo Bernardo, Rani K. Singh, Pradeep K. Javarayee, Jenny J. Lin, Jason C. Coryell, Shilpa B. Reddy, Abhinaya Ganesh, Michael A. Ciliberto, Debopam Samanta, Kristen H. Arredondo, Ahmad Marashly, Zachary M. Grinspan, Dallas Armstrong, Taylor J. Abel, Janelle Wagner, Derryl J. Miller, Fernando N. Galan, Michael Scott Perry","doi":"10.1002/cns3.70027","DOIUrl":"https://doi.org/10.1002/cns3.70027","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Rationale</h3>\u0000 \u0000 <p>Longer duration of epilepsy before surgery is a predictor of poor outcome. While referral delays of surgical candidates are well documented, factors causing delay during the presurgical evaluation remain unclear and may vary depending on institutional characteristics. By benchmarking the duration of presurgical evaluation across multiple centers and identifying patient and evaluation characteristics contributing to duration, we can ascertain best practices and address modifiable contributors to reduce delays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We queried the Pediatric Epilepsy Research Consortium Surgery Database, a prospective, observational multicenter study enrolling children 0–18 years at 27 US pediatric epilepsy centers, for all patients undergoing initial presurgical evaluation for drug-resistant epilepsy (DRE). We included patients with completed evaluations and data on duration from initiation of presurgical evaluation to final surgical decision. We compared patient characteristics and evaluation components between those with long duration evaluations (> 75% quartile) and those with short evaluations (< 25% quartile). Akaike information criteria selection identified variables associated with longer duration. From these, we developed a logistic prediction model for evaluation duration, using a random 80/20 training/testing split of the entire cohort. The model was tested among institutions with ≥ 10 patients in the cohort to assess its accuracy in predicting long durations. Linear models for each site assessed each variable's impact on duration. Variables with < 10% of the patient population at each site were excluded. Beta values were compared to identify intra- and inter-institution variability and to delineate institutions with the shortest added duration for each variable.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 2318 patients undergoing surgical evaluation, 1655 (71%) from 23 sites had complete data. Median evaluation duration was 8 weeks (interquartile range 3–22); 453 (27%) were short-duration evaluations and 414 (25%) were long-duration evaluations. Multiple patient and evaluation characteristics were associated with duration (Table 1). Table 6 provides the average duration each variable contributes to evaluation by site, highlighting the shortest durations compared with other groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Duration of presurgical evaluation for DRE can be accurately modeled using multiple patient characteristics and testing strategies commo","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"188-200"},"PeriodicalIF":0.0,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145100832","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>I thank Drs. Greeley and Anderst for taking the time to comment1 on my article “Witnessing abusive head trauma: Accidents show higher rates of intracranial pathologies than shaking.”2</p><p>The authors raise issues regarding the validity of comparing different data sets. They claim that “pediBIRN is a prospective, cohort study.” In fact, pediBIRN starts with an outcome (child with brain injury), then looks backward (using a clinician's judgment) to decide exposure (accident versus abuse). The PediBIRN authors themselves refer to the data as “strictly observational.”3 So whilst the registry of head injury cases is prosepective, it is <i>not</i> a prospective cohort study of exposures. The studies used in my article all have directionality of outcome to exposure.</p><p>Further, the base rate for shaking in my study is “witnessed shaking events,” regardless of which of the four studies4 the data were drawn from. I compiled a list of witnessed cases of shaking from the literature, and the number of such witnessed cases became the base rate in my study. I have not incorporated different base rates from the different studies into my study.</p><p>Nevertheless, the authors raise a central, crucial point regarding selection bias. Abusive head trauma (AHT) encompasses a spectrum—from a slap to violent shaking to forceful impact—just as accidental injury ranges from minor bumps to severe falls. Comparing rates of findings in all AHT cases versus all accidents is intractable. Any comparison of rates will be subject to selection bias, particularly selections that influence how severe was the accident and how severe was the abuse.</p><p>This is demonstrated in my previous article, “Retino-dural hemorrhages in infants are markers of degree of intracranial pathology not of violent shaking,”5 which shows that when studies claim certain findings are more common in AHT (i.e., specific for AHT), this apparent specificity stems from selection bias. Such studies typically compare severe cases of AHT with less severe accidental injuries. By contrast, when cases are matched for severity (as reflected by hypoxic brain injury), the findings supposedly associated with AHT instead correlate with the degree of brain injury—independent of cause or intent.</p><p>The other problem with articles that claim certain findings to be specific to AHT is the methods used for classification of cases as AHT, which are biased towards selecting cases with certain pathologies, creating a self-fulfilling prophecy. The motivation for my article was to restrict comparisons to cases that were witnessed, providing a more robust classification that does not suffer from such circular reasoning.</p><p>Unfortunately there is a paucity of such data, and my study required assembling data from different sources. This was explained as a limitation of the study, so I agree with the authors that a degree of caution is warranted in assessing the quoted rates, and I once again reiterate that it will be v
{"title":"Response to Comment on Witnessing Abusive Head Trauma: Accidents Show Higher Rates of Intracranial Pathologies Than Shaking","authors":"Chris B. Brook","doi":"10.1002/cns3.70018","DOIUrl":"https://doi.org/10.1002/cns3.70018","url":null,"abstract":"<p>I thank Drs. Greeley and Anderst for taking the time to comment1 on my article “Witnessing abusive head trauma: Accidents show higher rates of intracranial pathologies than shaking.”2</p><p>The authors raise issues regarding the validity of comparing different data sets. They claim that “pediBIRN is a prospective, cohort study.” In fact, pediBIRN starts with an outcome (child with brain injury), then looks backward (using a clinician's judgment) to decide exposure (accident versus abuse). The PediBIRN authors themselves refer to the data as “strictly observational.”3 So whilst the registry of head injury cases is prosepective, it is <i>not</i> a prospective cohort study of exposures. The studies used in my article all have directionality of outcome to exposure.</p><p>Further, the base rate for shaking in my study is “witnessed shaking events,” regardless of which of the four studies4 the data were drawn from. I compiled a list of witnessed cases of shaking from the literature, and the number of such witnessed cases became the base rate in my study. I have not incorporated different base rates from the different studies into my study.</p><p>Nevertheless, the authors raise a central, crucial point regarding selection bias. Abusive head trauma (AHT) encompasses a spectrum—from a slap to violent shaking to forceful impact—just as accidental injury ranges from minor bumps to severe falls. Comparing rates of findings in all AHT cases versus all accidents is intractable. Any comparison of rates will be subject to selection bias, particularly selections that influence how severe was the accident and how severe was the abuse.</p><p>This is demonstrated in my previous article, “Retino-dural hemorrhages in infants are markers of degree of intracranial pathology not of violent shaking,”5 which shows that when studies claim certain findings are more common in AHT (i.e., specific for AHT), this apparent specificity stems from selection bias. Such studies typically compare severe cases of AHT with less severe accidental injuries. By contrast, when cases are matched for severity (as reflected by hypoxic brain injury), the findings supposedly associated with AHT instead correlate with the degree of brain injury—independent of cause or intent.</p><p>The other problem with articles that claim certain findings to be specific to AHT is the methods used for classification of cases as AHT, which are biased towards selecting cases with certain pathologies, creating a self-fulfilling prophecy. The motivation for my article was to restrict comparisons to cases that were witnessed, providing a more robust classification that does not suffer from such circular reasoning.</p><p>Unfortunately there is a paucity of such data, and my study required assembling data from different sources. This was explained as a limitation of the study, so I agree with the authors that a degree of caution is warranted in assessing the quoted rates, and I once again reiterate that it will be v","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"255-256"},"PeriodicalIF":0.0,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145100940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>As the topic of abusive head trauma (AHT) has become a cause célèbre in some nonpediatric academic circles, we read the research article by Brook [<span>1</span>] with great interest. The research article reports on an effort to compare some of the findings typically associated with AHT between cases in which shaking was witnessed or admitted to those in which accidents were confirmed. Initially, it appears to be similar to prior studies comparing witnessed accidents with witnessed/admitted abuse [<span>2, 3</span>] but particularly focused on shaking as a reported mechanism. The author takes a unique approach in attempting to answer the question about the rate of findings between accidental and inflicted head injuries due to shaking. The author's chosen methodology contains several flaws, which are quite puzzling. We chose to specifically highlight two fundamental flaws that we feel undermine meaningful conclusions: the study designs of the chosen data sets and the populations being compared between the categories of cases.</p><p>The first concern is the data sets that were constructed. The author used four independent sources from which he has grouped participants into three categories: unconflicted witnessed accident, witnessed shaking, and unconflicted witnessed shaking. The first data set assembled (unconflicted witnessed accident) was of participants extracted from the PediBIRN study (www.pedibirn.com) and as reported in Hymel et al. [<span>4</span>]. PediBIRN is a prospective, cohort study of children younger than 3 years admitted to pediatric intensive care units for traumatic head injury. Children who are injured in accidents and admitted to an intensive care unit represent the most severe accidents only. The second data set assembled (unconflicted witnessed shaking) was from the Swedish National Patient Register and reported by Thiblin et al. [<span>5</span>]. This is a retrospective case series of infant victims of abuse identified by ICD-10 codes. In this data set, shaking is not an explicit variable, and the author only includes those participants in which shaking was expressly reported in the medical records. Records that did not include a reference to shaking (i.e., missing data) were treated the same as those in which shaking was specifically denied (i.e., shaking = “no”), likely resulting in undercounting of shaking. The author apparently includes the same 36 participants identified by Thiblin et al. [<span>5</span>]. If so, it is important to note that Thiblin et al. [<span>5</span>] has since received an “Expression of Concern” (similar to a “black box warning”) by the editors of <i>PLoS One</i>, in part due to “suitability of the study design to support the conclusions” [<span>6</span>]. The last category assembled (witnessed shaking) was from two separate sources, both reported in Feldman et al. [<span>7</span>]. The ExSTRA study was a prospective, multicenter, observational study of children younger than 10 years referred
{"title":"Commentary on Witnessing Abusive Head Trauma: Accidents Show Higher Rates of Intracranial Pathologies Than Shaking—Caution Is Warranted","authors":"Christopher Greeley, Jim Anderst","doi":"10.1002/cns3.70030","DOIUrl":"https://doi.org/10.1002/cns3.70030","url":null,"abstract":"<p>As the topic of abusive head trauma (AHT) has become a cause célèbre in some nonpediatric academic circles, we read the research article by Brook [<span>1</span>] with great interest. The research article reports on an effort to compare some of the findings typically associated with AHT between cases in which shaking was witnessed or admitted to those in which accidents were confirmed. Initially, it appears to be similar to prior studies comparing witnessed accidents with witnessed/admitted abuse [<span>2, 3</span>] but particularly focused on shaking as a reported mechanism. The author takes a unique approach in attempting to answer the question about the rate of findings between accidental and inflicted head injuries due to shaking. The author's chosen methodology contains several flaws, which are quite puzzling. We chose to specifically highlight two fundamental flaws that we feel undermine meaningful conclusions: the study designs of the chosen data sets and the populations being compared between the categories of cases.</p><p>The first concern is the data sets that were constructed. The author used four independent sources from which he has grouped participants into three categories: unconflicted witnessed accident, witnessed shaking, and unconflicted witnessed shaking. The first data set assembled (unconflicted witnessed accident) was of participants extracted from the PediBIRN study (www.pedibirn.com) and as reported in Hymel et al. [<span>4</span>]. PediBIRN is a prospective, cohort study of children younger than 3 years admitted to pediatric intensive care units for traumatic head injury. Children who are injured in accidents and admitted to an intensive care unit represent the most severe accidents only. The second data set assembled (unconflicted witnessed shaking) was from the Swedish National Patient Register and reported by Thiblin et al. [<span>5</span>]. This is a retrospective case series of infant victims of abuse identified by ICD-10 codes. In this data set, shaking is not an explicit variable, and the author only includes those participants in which shaking was expressly reported in the medical records. Records that did not include a reference to shaking (i.e., missing data) were treated the same as those in which shaking was specifically denied (i.e., shaking = “no”), likely resulting in undercounting of shaking. The author apparently includes the same 36 participants identified by Thiblin et al. [<span>5</span>]. If so, it is important to note that Thiblin et al. [<span>5</span>] has since received an “Expression of Concern” (similar to a “black box warning”) by the editors of <i>PLoS One</i>, in part due to “suitability of the study design to support the conclusions” [<span>6</span>]. The last category assembled (witnessed shaking) was from two separate sources, both reported in Feldman et al. [<span>7</span>]. The ExSTRA study was a prospective, multicenter, observational study of children younger than 10 years referred","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"253-254"},"PeriodicalIF":0.0,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Zumin Chen, Dea Garic, Yinuo Xu, Rachel G. Smith, Leigh Anne H. Weisenfeld, Sun Hyung Kim, Martin A. Styner, Joseph Piven, Benjamin D. Philpot, Heather C. Hazlett, Mark D. Shen
Background
Previous studies demonstrated that children with autism have enlarged volumes of extra-axial cerebrospinal fluid (EA-CSF) and an increased ratio of EA-CSF to brain volume, indicating that EA-CSF is disproportionally increased beyond macrocephaly often observed in autism. It is unknown whether EA-CSF is disproportionally enlarged in Angelman syndrome (AS), which shares phenotypic features with autism (sleep problems, seizures) but is characterized by microcephaly. This study examined EA-CSF and total cerebral volume (TCV) in AS children compared with neurotypical (NT) controls to test whether EA-CSF is disproportionally enlarged and is associated with sleep problems and seizures.
Methods
Magnetic resonance imaging scans were acquired in n = 29 AS (M[SD] = 6.95 ± 2.83 years) and n = 27 NT children (M[SD] = 7.96 ± 2.24). EA-CSF and TCV were compared using analysis of covariance (ANCOVA), controlling for age, sex, and group interactions. In AS, associations between EA-CSF, sleep quality, and seizure severity were evaluated by linear regression.
Results
Children with AS had 22% smaller TCV (p < 0.0001) yet nearly identical EA-CSF volumes (p = 0.35). The ratio of EA-CSF to TCV was 48% higher in AS (p < 0.0001). Increased EA-CSF ratio in AS was associated with sleep initiation problems (p = 0.002) and seizure severity (p = 0.032).
Conclusion
Children with AS have disproportionally higher EA-CSF volume than would be predicted by their smaller brain size. EA-CSF was associated with sleep problems and seizures, which impact quality of life and are target endpoints of current AS clinical trials. Excessive CSF suggests that CSF circulation might be perturbed in AS, which could have implications for brain waste clearance and impact the biodistribution of AS therapies delivered via CSF.
{"title":"Increased Extra-Axial Cerebrospinal Fluid Volume in Children With Angelman Syndrome: Links to Sleep Problems and Seizures","authors":"Zumin Chen, Dea Garic, Yinuo Xu, Rachel G. Smith, Leigh Anne H. Weisenfeld, Sun Hyung Kim, Martin A. Styner, Joseph Piven, Benjamin D. Philpot, Heather C. Hazlett, Mark D. Shen","doi":"10.1002/cns3.70024","DOIUrl":"10.1002/cns3.70024","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Previous studies demonstrated that children with autism have enlarged volumes of extra-axial cerebrospinal fluid (EA-CSF) and an increased ratio of EA-CSF to brain volume, indicating that EA-CSF is disproportionally increased beyond macrocephaly often observed in autism. It is unknown whether EA-CSF is disproportionally enlarged in Angelman syndrome (AS), which shares phenotypic features with autism (sleep problems, seizures) but is characterized by microcephaly. This study examined EA-CSF and total cerebral volume (TCV) in AS children compared with neurotypical (NT) controls to test whether EA-CSF is disproportionally enlarged and is associated with sleep problems and seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Magnetic resonance imaging scans were acquired in <i>n</i> = 29 AS (M[SD] = 6.95 ± 2.83 years) and <i>n</i> = 27 NT children (M[SD] = 7.96 ± 2.24). EA-CSF and TCV were compared using analysis of covariance (ANCOVA), controlling for age, sex, and group interactions. In AS, associations between EA-CSF, sleep quality, and seizure severity were evaluated by linear regression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Children with AS had 22% smaller TCV (<i>p</i> < 0.0001) yet nearly identical EA-CSF volumes (<i>p</i> = 0.35). The ratio of EA-CSF to TCV was 48% higher in AS (<i>p</i> < 0.0001). Increased EA-CSF ratio in AS was associated with sleep initiation problems (<i>p</i> = 0.002) and seizure severity (<i>p</i> = 0.032).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Children with AS have disproportionally higher EA-CSF volume than would be predicted by their smaller brain size. EA-CSF was associated with sleep problems and seizures, which impact quality of life and are target endpoints of current AS clinical trials. Excessive CSF suggests that CSF circulation might be perturbed in AS, which could have implications for brain waste clearance and impact the biodistribution of AS therapies delivered via CSF.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"3 3","pages":"165-175"},"PeriodicalIF":0.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12356226/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144980725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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