Douglas P. Munoz, Brian J. White, Donald C. Brien, Kajaal Parbhoo, Carmen Yea, E. Ann Yeh
Objective
This study measured eye movements in children with a history of opsoclonus-myoclonus ataxia syndrome in order to identify abnormalities in saccade and pupil behavior that map onto specific alterations in brainstem pathways.
Methods
We used video-based eye tracking while participants freely viewed 10 min of short (2–4 s) video clips without instructions. Clip transitions represented a large visual perturbation and we quantified multiple characteristics of saccade and pupil responses following these transitions in 13 children recovering from opsoclonus-myoclonus and 13 healthy, age-matched control participants.
Results
The frequency of saccades and distribution of fixation durations differed between the groups. Following the clip transitions, children recovering from opsoclonus-myoclonus ataxia syndrome exhibited longer time to initiate saccades, leading to a delay in harvesting visual information. Clip transitions to lighter clips produced similar pupil constriction responses in the two groups. However, clip transitions to darker clips produced dilation responses that were initiated earlier and of greater magnitude in opsoclonus-myoclonus ataxia syndrome, suggesting removal or suppression of a signal that delays dilation.
Interpretation
Children with a history of opsoclonus-myoclonus ataxia syndrome demonstrated key abnormalities in saccade and pupil metrics. We propose a novel hypothesis in which dysfunction in the pathway from the superior colliculus to the mesencephalic and pontine reticular formation that houses the saccade and pupil premotor circuits could produce these results.
{"title":"Saccade and pupil changes in children recovering from opsoclonus-myoclonus ataxia syndrome reveal midbrain alterations in oculomotor circuits","authors":"Douglas P. Munoz, Brian J. White, Donald C. Brien, Kajaal Parbhoo, Carmen Yea, E. Ann Yeh","doi":"10.1002/cns3.20078","DOIUrl":"10.1002/cns3.20078","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study measured eye movements in children with a history of opsoclonus-myoclonus ataxia syndrome in order to identify abnormalities in saccade and pupil behavior that map onto specific alterations in brainstem pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used video-based eye tracking while participants freely viewed 10 min of short (2–4 s) video clips without instructions. Clip transitions represented a large visual perturbation and we quantified multiple characteristics of saccade and pupil responses following these transitions in 13 children recovering from opsoclonus-myoclonus and 13 healthy, age-matched control participants.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The frequency of saccades and distribution of fixation durations differed between the groups. Following the clip transitions, children recovering from opsoclonus-myoclonus ataxia syndrome exhibited longer time to initiate saccades, leading to a delay in harvesting visual information. Clip transitions to lighter clips produced similar pupil constriction responses in the two groups. However, clip transitions to darker clips produced dilation responses that were initiated earlier and of greater magnitude in opsoclonus-myoclonus ataxia syndrome, suggesting removal or suppression of a signal that delays dilation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Children with a history of opsoclonus-myoclonus ataxia syndrome demonstrated key abnormalities in saccade and pupil metrics. We propose a novel hypothesis in which dysfunction in the pathway from the superior colliculus to the mesencephalic and pontine reticular formation that houses the saccade and pupil premotor circuits could produce these results.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 3","pages":"212-224"},"PeriodicalIF":0.0,"publicationDate":"2024-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141671789","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}
Rutu M. Dave, Janetta Arellano, Charles Grose, Rachel Pearson
Objective
Herpes simplex virus (HSV) encephalitis can be associated with many secondary neurological complications, but having multiple episodes of recurrent neurological complications is rare in an individual. Understanding the course of each complication can reduce time to diagnosis and adequate treatment. Additionally, we postulate the role of RNF213 mutation in HSV susceptibility.
Methods
We describe a unique presentation of HSV-1 encephalitis in an infant with a pathogenic RNF213 mutation who went on to develop multiple rare neurological complications over the course of her illness.
Results
Our patient was first diagnosed with neonatal HSV-1 encephalitis at age 2 weeks. She had recurrence of HSV encephalitis (HSE) with associated vasculopathy that led to right middle cerebral artery and posterior cerebral artery infarctions at 13 months, and then later developed post-HSE anti-N-methyl- d-aspartate receptor encephalitis. All of this occurred concomitant with RNF213 mutation.
Interpretation
This patient demonstrates that, though rare, multiple neurological complications can occur in a single person, thus highlighting the importance of close surveillance of patients with a history of neonatal HSE and pursuing a broad differential in patients with subtle or recurrent symptoms. Furthermore, we propose a potential role of RNF213 mutation in the pathogenesis of our patient's multiple medical conditions.
{"title":"Recurrent encephalitis and stroke following cessation of acyclovir prophylaxis in a patient with neonatal herpes simplex virus with RNF213 mutation","authors":"Rutu M. Dave, Janetta Arellano, Charles Grose, Rachel Pearson","doi":"10.1002/cns3.20079","DOIUrl":"https://doi.org/10.1002/cns3.20079","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Herpes simplex virus (HSV) encephalitis can be associated with many secondary neurological complications, but having multiple episodes of recurrent neurological complications is rare in an individual. Understanding the course of each complication can reduce time to diagnosis and adequate treatment. Additionally, we postulate the role of <i>RNF213</i> mutation in HSV susceptibility.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We describe a unique presentation of HSV-1 encephalitis in an infant with a pathogenic <i>RNF213</i> mutation who went on to develop multiple rare neurological complications over the course of her illness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our patient was first diagnosed with neonatal HSV-1 encephalitis at age 2 weeks. She had recurrence of HSV encephalitis (HSE) with associated vasculopathy that led to right middle cerebral artery and posterior cerebral artery infarctions at 13 months, and then later developed post-HSE anti-<i>N</i>-methyl-\u0000<span>d</span>-aspartate receptor encephalitis. All of this occurred concomitant with <i>RNF213</i> mutation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This patient demonstrates that, though rare, multiple neurological complications can occur in a single person, thus highlighting the importance of close surveillance of patients with a history of neonatal HSE and pursuing a broad differential in patients with subtle or recurrent symptoms. Furthermore, we propose a potential role of <i>RNF213</i> mutation in the pathogenesis of our patient's multiple medical conditions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 3","pages":"235-241"},"PeriodicalIF":0.0,"publicationDate":"2024-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320713","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}
Alexandra Santana Almansa, Stephen M. Chrzanowski, Farrah Rajabi, Megan Day-Lewis, Pui Y. Lee, Hart G. W. Lidov, Laura L. Lehman, Leslie H. Hayes
Introduction
There are overlapping features between inflammatory myopathies and muscular dystrophies, particularly laminopathies. Key features that characterize laminopathies include axial and proximal weakness, contractures, and cardiac abnormalities.
Methods/Results
A 12-year-old girl diagnosed with juvenile dermatomyositis as a child presented with cardiac failure and was found to have an LMNA likely pathogenic variant, with a phenotype most consistent with Emery–Dreifuss muscular dystrophy type 2.
Discussion
The spectrum of clinical features of LMNA-related muscular dystrophies can mimic or present with inflammatory myopathy-like features. Early identification of LMNA-related muscular dystrophies is crucial to ensure appropriate cardiac screening and prevent devastating cardiac complications.
{"title":"LMNA-related muscular dystrophy presenting as an inflammatory myopathy","authors":"Alexandra Santana Almansa, Stephen M. Chrzanowski, Farrah Rajabi, Megan Day-Lewis, Pui Y. Lee, Hart G. W. Lidov, Laura L. Lehman, Leslie H. Hayes","doi":"10.1002/cns3.20075","DOIUrl":"https://doi.org/10.1002/cns3.20075","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>There are overlapping features between inflammatory myopathies and muscular dystrophies, particularly laminopathies. Key features that characterize laminopathies include axial and proximal weakness, contractures, and cardiac abnormalities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods/Results</h3>\u0000 \u0000 <p>A 12-year-old girl diagnosed with juvenile dermatomyositis as a child presented with cardiac failure and was found to have an <i>LMNA</i> likely pathogenic variant, with a phenotype most consistent with Emery–Dreifuss muscular dystrophy type 2.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Discussion</h3>\u0000 \u0000 <p>The spectrum of clinical features of <i>LMNA</i>-related muscular dystrophies can mimic or present with inflammatory myopathy-like features. Early identification of <i>LMNA</i>-related muscular dystrophies is crucial to ensure appropriate cardiac screening and prevent devastating cardiac complications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 3","pages":"242-247"},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320648","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}
Shermila Pia, Elizabeth Stackhouse, Shehanaz Ellika
This 21-month-old boy with a history of multiple febrile seizures presented in refractory febrile status epilepticus. He had rhinorrhea and cough and tested positive for influenza type A. Cerebrospinal fluid analysis showed an elevated protein of 49 mg/dL (reference 10–32 mg/dL) with normal cells, glucose, lactate, meningitis/encephalitis, and autoimmune encephalitis panels. Magnetic resonance imaging revealed T2 hyperintensity, diffusion restriction, and susceptibility signal loss involving the bilateral cerebral cortices, cerebral white matter, thalami, basal ganglia, cerebellum, and brainstem (Figure 1). Metabolic screening and rapid whole-genome sequencing including RANBP2 were unrevealing.
He was diagnosed with acute necrotizing encephalopathy (ANE) due to influenza A. He was treated with intravenous immunoglobulin (IVIG) and high-dose methylprednisolone. His course was complicated by severe paroxysmal sympathetic hyperactivity and prolonged hypoxic respiratory failure. Two months after the initial presentation, he had cortical blindness, diffuse spasticity, and dystonia without purposeful movements.
ANE is a rare but severe parainfectious disorder predominantly occuring in the pediatric age group and is associated with significant neurological morbidity and mortality.1, 2 First described in 1997,3 ANE typically presents with seizure and encephalopathy concomitant with viral illness. Influenza type A is the most commonly identified pathogen,1 but many others have been implicated. More recently, familial/genetic ANE has been reported in association with pathogenic variants in RANBP2, and genetic testing is now recommended in the evaluation of these patients.1, 2 Radiographically, ANE is characterized by symmetric T2 hyperintensity, diffusion restriction, and susceptibility signal loss in bilateral cerebral cortices, thalami, basal ganglia, cerebral white matter, brainstem, and cerebellar hemispheres.4, 5 A characteristic trilaminar pattern of diffusion restriction on the apparent diffusion coefficient map in the thalami is specific for ANE,4, 5 with the core demonstrating high signal intensity, pericore showing low signal intensity, and peripheral zone of high signal intensity, corresponding with pathologic findings of hemorrhagic necrosis in the core, pericore cytotoxic edema, and perilesional vasogenic edema.5 The prognosis is poor, with less than 10% full recovery, nearly 30% mortality, and significant neurological morbidity in survivors.1, 2 Early treatment with high-dose steroids is associated with improved outcomes.
Shermila Pia: Conceptualization; writing—original draft; writing—review & editing. Elizabeth Stackhouse: Writing—review & editing. Shehanaz Ellika: Data curation; supervisi
{"title":"A rare and devastating etiology of febrile seizure","authors":"Shermila Pia, Elizabeth Stackhouse, Shehanaz Ellika","doi":"10.1002/cns3.20080","DOIUrl":"https://doi.org/10.1002/cns3.20080","url":null,"abstract":"<p>This 21-month-old boy with a history of multiple febrile seizures presented in refractory febrile status epilepticus. He had rhinorrhea and cough and tested positive for influenza type A. Cerebrospinal fluid analysis showed an elevated protein of 49 mg/dL (reference 10–32 mg/dL) with normal cells, glucose, lactate, meningitis/encephalitis, and autoimmune encephalitis panels. Magnetic resonance imaging revealed T2 hyperintensity, diffusion restriction, and susceptibility signal loss involving the bilateral cerebral cortices, cerebral white matter, thalami, basal ganglia, cerebellum, and brainstem (Figure 1). Metabolic screening and rapid whole-genome sequencing including <i>RANBP2</i> were unrevealing.</p><p>He was diagnosed with acute necrotizing encephalopathy (ANE) due to influenza A. He was treated with intravenous immunoglobulin (IVIG) and high-dose methylprednisolone. His course was complicated by severe paroxysmal sympathetic hyperactivity and prolonged hypoxic respiratory failure. Two months after the initial presentation, he had cortical blindness, diffuse spasticity, and dystonia without purposeful movements.</p><p>ANE is a rare but severe parainfectious disorder predominantly occuring in the pediatric age group and is associated with significant neurological morbidity and mortality.<span><sup>1, 2</sup></span> First described in 1997,<span><sup>3</sup></span> ANE typically presents with seizure and encephalopathy concomitant with viral illness. Influenza type A is the most commonly identified pathogen,<span><sup>1</sup></span> but many others have been implicated. More recently, familial/genetic ANE has been reported in association with pathogenic variants in <i>RANBP2</i>, and genetic testing is now recommended in the evaluation of these patients.<span><sup>1, 2</sup></span> Radiographically, ANE is characterized by symmetric T2 hyperintensity, diffusion restriction, and susceptibility signal loss in bilateral cerebral cortices, thalami, basal ganglia, cerebral white matter, brainstem, and cerebellar hemispheres.<span><sup>4, 5</sup></span> A characteristic trilaminar pattern of diffusion restriction on the apparent diffusion coefficient map in the thalami is specific for ANE,<span><sup>4, 5</sup></span> with the core demonstrating high signal intensity, pericore showing low signal intensity, and peripheral zone of high signal intensity, corresponding with pathologic findings of hemorrhagic necrosis in the core, pericore cytotoxic edema, and perilesional vasogenic edema.<span><sup>5</sup></span> The prognosis is poor, with less than 10% full recovery, nearly 30% mortality, and significant neurological morbidity in survivors.<span><sup>1, 2</sup></span> Early treatment with high-dose steroids is associated with improved outcomes.</p><p><b>Shermila Pia</b>: Conceptualization; writing—original draft; writing—review & editing. <b>Elizabeth Stackhouse</b>: Writing—review & editing. <b>Shehanaz Ellika</b>: Data curation; supervisi","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 3","pages":"251-252"},"PeriodicalIF":0.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320844","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}
Aravindhan Veerapandiyan, Anne M. Connolly, Katherine D. Mathews, Stanley Nelson, Craig McDonald, Richard S. Finkel, Vettaikorumakankav Vedanarayanan, Cuixia Tian, Susan Apkon, Julie A. Parsons, Jonathan H. Soslow, William Bryan Burnette, Kaitlin Y. Batley, Susan T. Iannaccone, Carolina Tesi Rocha, Kevin M. Flanigan, Diana Bharucha-Goebel, Sarah Wright, Migvis Monduy, Simona Treidler, Ashutosh Kumar, Nancy L. Kuntz, Vamshi K. Rao, Rachel Schrader, Saunder M. Bernes, Vikki Ann Stefans, Jena M. Krueger, Marcia V. Felker, Omer Abdul Hamid, Arpita Lakhotia, Susan Matesanz, Partha S. Ghosh, Natalie Katz, Hoda Abdel-Hamid, Chamindra G. Laverty, Bo Hoon Lee, Amy Harper, Leigh Ramos-Platt, Diana Castro, Russell J. Butterfield, Crystal M. Proud, Craig M. Zaidman, Emma Ciafaloni
<p>Duchenne muscular dystrophy (DMD) is a rare, X-linked, progressive, degenerative muscle disease due to pathogenic variants in the <i>DMD</i> gene resulting in absence of functional dystrophin protein.<span><sup>1</sup></span> Patients with DMD have irreversible muscle damage that begins at birth, and there is histologic evidence of disease progression with progressive inflammation and fibrosis within the first years of life.<span><sup>2</sup></span> Proactive interdisciplinary care, corticosteroids, and advances in disease-modifying treatments have changed the trajectory of the disease, leading to slower progression and improving life expectancy. This statement from clinicians who care for patients with DMD aims to provide insights into the current therapeutic landscape and access to novel therapies for DMD.</p><p>Recent years have seen a remarkable number of clinical trials to evaluate the disease-modifying ability of novel therapies for DMD. In addition to corticosteroids (deflazacort and vamorolone), several gene-targeted therapies were approved by the U.S. Food and Drug Administration (FDA). These include exon-skipping agents (eteplirsen, golodirsen, viltolarsen, and casimersen) that restore the reading frame of <i>DMD</i> transcripts and delandistrogene moxeparvovec-rokl, an adeno-associated virus–based microdystrophin gene transfer therapy. Further, there is a robust pipeline of targeted gene-based therapies and treatments targeting downstream pathways such as regulating muscle fiber degeneration and regeneration.<span><sup>3-5</sup></span> While existing treatments offer benefits by delaying or slowing disease progression, none provide a cure. The emergence of treatments that target the disease through multiple mechanisms underscores the importance of assessing combination therapies for DMD, akin to approaches used in treating oncological disorders. Given the progressive and irreversible nature of muscle degeneration in DMD, timely initiation of treatments is crucial. Delaying treatment initiation could result in permanent loss of motor function, underscoring the urgency of prompt intervention.</p><p>DMD is a severe and progressive rare disorder with significant gaps in available treatments. The low incidence and heterogeneity in genotypes and phenotypes pose challenges in conducting traditional large-scale placebo-controlled trials in a reasonable amount of time. The restoration of shortened functional forms of dystrophin serve as biomarkers representing appropriate endpoints in the FDA's accelerated approval pathway. This pathway allows FDA approval of drugs that treat serious conditions with unmet medical need based on a surrogate endpoint that is reasonably likely to predict clinical benefit.<span><sup>6</sup></span> It is important to note that therapies approved under accelerated approval are still required to undergo robust phase 3 confirmatory trials, providing data for traditional approval. There are currently 27 drugs approved
{"title":"Access to novel therapies for Duchenne muscular dystrophy—Insights from expert treating physicians","authors":"Aravindhan Veerapandiyan, Anne M. Connolly, Katherine D. Mathews, Stanley Nelson, Craig McDonald, Richard S. Finkel, Vettaikorumakankav Vedanarayanan, Cuixia Tian, Susan Apkon, Julie A. Parsons, Jonathan H. Soslow, William Bryan Burnette, Kaitlin Y. Batley, Susan T. Iannaccone, Carolina Tesi Rocha, Kevin M. Flanigan, Diana Bharucha-Goebel, Sarah Wright, Migvis Monduy, Simona Treidler, Ashutosh Kumar, Nancy L. Kuntz, Vamshi K. Rao, Rachel Schrader, Saunder M. Bernes, Vikki Ann Stefans, Jena M. Krueger, Marcia V. Felker, Omer Abdul Hamid, Arpita Lakhotia, Susan Matesanz, Partha S. Ghosh, Natalie Katz, Hoda Abdel-Hamid, Chamindra G. Laverty, Bo Hoon Lee, Amy Harper, Leigh Ramos-Platt, Diana Castro, Russell J. Butterfield, Crystal M. Proud, Craig M. Zaidman, Emma Ciafaloni","doi":"10.1002/cns3.20076","DOIUrl":"10.1002/cns3.20076","url":null,"abstract":"<p>Duchenne muscular dystrophy (DMD) is a rare, X-linked, progressive, degenerative muscle disease due to pathogenic variants in the <i>DMD</i> gene resulting in absence of functional dystrophin protein.<span><sup>1</sup></span> Patients with DMD have irreversible muscle damage that begins at birth, and there is histologic evidence of disease progression with progressive inflammation and fibrosis within the first years of life.<span><sup>2</sup></span> Proactive interdisciplinary care, corticosteroids, and advances in disease-modifying treatments have changed the trajectory of the disease, leading to slower progression and improving life expectancy. This statement from clinicians who care for patients with DMD aims to provide insights into the current therapeutic landscape and access to novel therapies for DMD.</p><p>Recent years have seen a remarkable number of clinical trials to evaluate the disease-modifying ability of novel therapies for DMD. In addition to corticosteroids (deflazacort and vamorolone), several gene-targeted therapies were approved by the U.S. Food and Drug Administration (FDA). These include exon-skipping agents (eteplirsen, golodirsen, viltolarsen, and casimersen) that restore the reading frame of <i>DMD</i> transcripts and delandistrogene moxeparvovec-rokl, an adeno-associated virus–based microdystrophin gene transfer therapy. Further, there is a robust pipeline of targeted gene-based therapies and treatments targeting downstream pathways such as regulating muscle fiber degeneration and regeneration.<span><sup>3-5</sup></span> While existing treatments offer benefits by delaying or slowing disease progression, none provide a cure. The emergence of treatments that target the disease through multiple mechanisms underscores the importance of assessing combination therapies for DMD, akin to approaches used in treating oncological disorders. Given the progressive and irreversible nature of muscle degeneration in DMD, timely initiation of treatments is crucial. Delaying treatment initiation could result in permanent loss of motor function, underscoring the urgency of prompt intervention.</p><p>DMD is a severe and progressive rare disorder with significant gaps in available treatments. The low incidence and heterogeneity in genotypes and phenotypes pose challenges in conducting traditional large-scale placebo-controlled trials in a reasonable amount of time. The restoration of shortened functional forms of dystrophin serve as biomarkers representing appropriate endpoints in the FDA's accelerated approval pathway. This pathway allows FDA approval of drugs that treat serious conditions with unmet medical need based on a surrogate endpoint that is reasonably likely to predict clinical benefit.<span><sup>6</sup></span> It is important to note that therapies approved under accelerated approval are still required to undergo robust phase 3 confirmatory trials, providing data for traditional approval. There are currently 27 drugs approved","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 3","pages":"184-188"},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20076","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141357504","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}
Elizabeth Pickup, Christopher Redmond, Matthew A. Sherman, Lakshmi Ramachandran Nair, Sangeeta Sule, Elizabeth Wells, Alexandra B. Kornbluh
Objective
Overlap syndromes have been described between N-methyl- d-aspartate receptor encephalitis (NMDARE) and other neuroinflammatory conditions, although rarely involving neurosarcoidosis. Molecularly targeted immunotherapy may be helpful in the empiric treatment of these conditions.
Methods
We describe a 9-year-old boy with new-onset seizures and worsening encephalopathy.
Results
Initial evaluation was concerning for neurosarcoidosis, including elevated cerebrospinal fluid (CSF) and serum angiotensin-converting enzyme and leptomeningeal with multiple cranial nerve enhancement on magnetic resonance imaging. CSF and serum cytokine profiles were used to choose targeted empiric immunotherapy, and the boy's seizure burden and encephalopathy improved after treatment with tocilizumab. The NMDA receptor antibody titer was later found to be elevated, raising suspicion for a novel overlap syndrome.
Interpretation
Our patient met the criteria for definite NMDARE and possible neurosarcoidosis. Given the mixed radiographic and serologic markers in this child, cytokine levels were used to direct the choice of empiric treatment, resulting in excellent clinical response. This case suggests that targeted immunotherapy informed by cytokine testing may be helpful in cases of high-acuity pediatric neuroinflammatory disease with limited diagnostic clarity.
{"title":"Molecularly targeted immunotherapy used to treat a novel overlap syndrome of pediatric N-methyl-\u0000d-aspartate receptor encephalitis (NMDARE) and possible neurosarcoidosis","authors":"Elizabeth Pickup, Christopher Redmond, Matthew A. Sherman, Lakshmi Ramachandran Nair, Sangeeta Sule, Elizabeth Wells, Alexandra B. Kornbluh","doi":"10.1002/cns3.20074","DOIUrl":"10.1002/cns3.20074","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Overlap syndromes have been described between <i>N</i>-methyl-\u0000<span>d</span>-aspartate receptor encephalitis (NMDARE) and other neuroinflammatory conditions, although rarely involving neurosarcoidosis. Molecularly targeted immunotherapy may be helpful in the empiric treatment of these conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We describe a 9-year-old boy with new-onset seizures and worsening encephalopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Initial evaluation was concerning for neurosarcoidosis, including elevated cerebrospinal fluid (CSF) and serum angiotensin-converting enzyme and leptomeningeal with multiple cranial nerve enhancement on magnetic resonance imaging. CSF and serum cytokine profiles were used to choose targeted empiric immunotherapy, and the boy's seizure burden and encephalopathy improved after treatment with tocilizumab. The NMDA receptor antibody titer was later found to be elevated, raising suspicion for a novel overlap syndrome.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our patient met the criteria for definite NMDARE and possible neurosarcoidosis. Given the mixed radiographic and serologic markers in this child, cytokine levels were used to direct the choice of empiric treatment, resulting in excellent clinical response. This case suggests that targeted immunotherapy informed by cytokine testing may be helpful in cases of high-acuity pediatric neuroinflammatory disease with limited diagnostic clarity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 2","pages":"168-175"},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141272261","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}
Brooke Kimbrell, Kieran D. McKenney, SangEun Yeom, Isabelle Iannotti, Alyssa Day, Kelly Harmon, Alison Sebold, Lindsay Smegal, Katherine Kaplan, Cassie Daisy, Rama Aldakhlallah, Michael Taylor, Anna Pinto, Adrienne Hammill, Marsha A. Moses, Anne Comi
Objective
This study identified biomarkers of neurological outcome in Sturge-Weber syndrome (SWS) via urine angiogenic factors and captured longitudinally derived natural history data within an SWS cohort.
Methods
This longitudinal, prospective, multicentered study of 61 people with SWS aged 0.4–55 years reports port-wine birthmark score, Neuroscore, Neuro-Quality of Life, and urine angiogenic factors over a two-year period.
Results
Cognitive Neuroscore worsened over time for children aged 0–2 years. Male sex was associated with worsening Cognitive Function Neuroscore during the study. Age of seizure onset before 2 years was strongly associated with worse Neuroscore. Children with SWS had low Neuro-Quality of Life related to cognitive function. Seizure severity, male sex, and earlier age of seizure onset were associated with worse Neuro-Quality of Life in school-aged children. Children with SWS have elevated basic fibroblast growth factor in their urine compared with controls, whereas higher vascular endothelial growth factor was associated with better Neuroscore.
Interpretation
This study is the first multicenter, prospective, and longitudinal study of people with SWS. It identifies significant clinical prognostic factors such as age of seizure onset and male sex, informs symptom progression over time by age group, and suggests that further study of angiogenic mechanisms and potential biomarkers are needed.
{"title":"Longitudinal prospective study of Sturge–Weber syndrome urine angiogenic factors and neurological outcome","authors":"Brooke Kimbrell, Kieran D. McKenney, SangEun Yeom, Isabelle Iannotti, Alyssa Day, Kelly Harmon, Alison Sebold, Lindsay Smegal, Katherine Kaplan, Cassie Daisy, Rama Aldakhlallah, Michael Taylor, Anna Pinto, Adrienne Hammill, Marsha A. Moses, Anne Comi","doi":"10.1002/cns3.20071","DOIUrl":"10.1002/cns3.20071","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study identified biomarkers of neurological outcome in Sturge-Weber syndrome (SWS) via urine angiogenic factors and captured longitudinally derived natural history data within an SWS cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This longitudinal, prospective, multicentered study of 61 people with SWS aged 0.4–55 years reports port-wine birthmark score, Neuroscore, Neuro-Quality of Life, and urine angiogenic factors over a two-year period.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Cognitive Neuroscore worsened over time for children aged 0–2 years. Male sex was associated with worsening Cognitive Function Neuroscore during the study. Age of seizure onset before 2 years was strongly associated with worse Neuroscore. Children with SWS had low Neuro-Quality of Life related to cognitive function. Seizure severity, male sex, and earlier age of seizure onset were associated with worse Neuro-Quality of Life in school-aged children. Children with SWS have elevated basic fibroblast growth factor in their urine compared with controls, whereas higher vascular endothelial growth factor was associated with better Neuroscore.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study is the first multicenter, prospective, and longitudinal study of people with SWS. It identifies significant clinical prognostic factors such as age of seizure onset and male sex, informs symptom progression over time by age group, and suggests that further study of angiogenic mechanisms and potential biomarkers are needed.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 2","pages":"120-134"},"PeriodicalIF":0.0,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141269533","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}
Klaus Werner, Trevor Gerson, Alit Stark-Inbar, Sharon Shmuely, Alon Ironi, Christina L. Szperka, Andrew D. Hershey
Objectives
Migraine is a prevalent neurological disorder severely impacting children and adolescents, yet only one pharmacological treatment is approved for ages 6−12 years. Remote electrical neuromodulation (REN) is a nonpharmacological, prescribed, wearable device cleared by the Food and Drug Administration for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. This study evaluates REN's safety and efficacy in ages 6−11 years.
Methods
Prospective acute treatment of migraine data were collected through the REN device (Nerivio) smartphone application. Endpoints were device safety (primary); consistent treatment efficacy (headache pain, functional disability, associated migraine symptoms), and REN-medication combinations 2 h post-treatment.
Results
Children (n = 293), median age 11 years (interquartile range = 9−11), 73.7% girls, conducted 5493 REN treatments. No adverse events were reported. Efficacy in at least 50% of REN treatments was calculated from all patients who voluntarily reported pain levels, symptoms, and/or disability at treatment onset and at 2 h post-treatment, with 72.2% (13/18) of patients reporting pain relief, 36.0% (9/25) pain freedom, 83.3% (15/18) functional disability relief, and 38.9% (7/18) functional disability freedom. Migraine-associated symptoms disappeared in at least 50% of REN treatments in 70.0% (7/10) of patients for nausea/vomiting, 50.0% (4/8) phonophobia, and 22.2% (2/9) photophobia; 63.6% (7/11) reported freedom from at least one associated symptom. REN was used as a standalone treatment, with over-the-counter medications, and with prescribed headache medications in 45.4%, 34.4%, and 20.9% of treatments, respectively.
Interpretation
REN may serve as a safe and efficacious acute treatment of migraine for children. Providers and families seeking a safe, effective, pill- and needle-free treatment option for children suffering from migraine may consider REN.
{"title":"Acute treatment of migraine in children aged 6−11: Real-world analysis of remote electrical neuromodulation (REN)","authors":"Klaus Werner, Trevor Gerson, Alit Stark-Inbar, Sharon Shmuely, Alon Ironi, Christina L. Szperka, Andrew D. Hershey","doi":"10.1002/cns3.20073","DOIUrl":"10.1002/cns3.20073","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Migraine is a prevalent neurological disorder severely impacting children and adolescents, yet only one pharmacological treatment is approved for ages 6−12 years. Remote electrical neuromodulation (REN) is a nonpharmacological, prescribed, wearable device cleared by the Food and Drug Administration for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. This study evaluates REN's safety and efficacy in ages 6−11 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Prospective acute treatment of migraine data were collected through the REN device (Nerivio) smartphone application. Endpoints were device safety (primary); consistent treatment efficacy (headache pain, functional disability, associated migraine symptoms), and REN-medication combinations 2 h post-treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Children (<i>n</i> = 293), median age 11 years (interquartile range = 9−11), 73.7% girls, conducted 5493 REN treatments. No adverse events were reported. Efficacy in at least 50% of REN treatments was calculated from all patients who voluntarily reported pain levels, symptoms, and/or disability at treatment onset and at 2 h post-treatment, with 72.2% (13/18) of patients reporting pain relief, 36.0% (9/25) pain freedom, 83.3% (15/18) functional disability relief, and 38.9% (7/18) functional disability freedom. Migraine-associated symptoms disappeared in at least 50% of REN treatments in 70.0% (7/10) of patients for nausea/vomiting, 50.0% (4/8) phonophobia, and 22.2% (2/9) photophobia; 63.6% (7/11) reported freedom from at least one associated symptom. REN was used as a standalone treatment, with over-the-counter medications, and with prescribed headache medications in 45.4%, 34.4%, and 20.9% of treatments, respectively.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>REN may serve as a safe and efficacious acute treatment of migraine for children. Providers and families seeking a safe, effective, pill- and needle-free treatment option for children suffering from migraine may consider REN.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 2","pages":"135-145"},"PeriodicalIF":0.0,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141117394","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}
Carlos Lastra, Robert Abrahams, Gregory Anash, Kyle Prisby, Luz Goyco-Ortiz, Andrea Melean, Rosanne Moreno, Alexander Schramm
Objective
This study assessed anxiety levels in children during the COVID-19 pandemic and explored how factors related to COVID-19 may have affected the prevalence of anxiety disorders among the pediatric population.
Methods
Childhood anxiety symptoms were assessed at various pediatric practices in Central New Jersey between July 2021 and September 2022. The sample comprised 476 children and adolescents aged 8–17 who participated in the Screen for Child Anxiety Related Disorders (SCARED) questionnaire, administered at their annual well-child visits. Participants included both the child and the caregiver. The anxiety prevalence was compared with prepandemic standards published by the Centers for Disease Control (CDC).
Results
The prevalence of anxiety for children aged 8–17 years (28.3%) was greater than prepandemic levels (7.1%; p < 0.0001). Among children aged 8–11, anxiety increased from 6.6% to 38.1% (p < 0.0001), while for children aged 11–17, anxiety increased from 10.5% to 22.2% (p < 0.0001). Previously diagnosed anxiety was a strong predictor of a high anxiety score on the questionnaire (mean = 28.95) compared with children without a history of anxiety (mean = 17.65; p < 0.001). Furthermore, a disparity was identified in the responses between the child and the caregiver questionnaires (p < 0.0001).
Conclusion
This study shows that children's anxiety levels increased during the COVID-19 pandemic. Moreover, an inconsistency was found between children self-reporting anxiety and caregivers underreporting their child's anxiety. These findings underscore the need for targeted support for those affected, especially children with a history of anxiety.
{"title":"Assessment of anxiety in children during the COVID-19 pandemic","authors":"Carlos Lastra, Robert Abrahams, Gregory Anash, Kyle Prisby, Luz Goyco-Ortiz, Andrea Melean, Rosanne Moreno, Alexander Schramm","doi":"10.1002/cns3.20072","DOIUrl":"10.1002/cns3.20072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study assessed anxiety levels in children during the COVID-19 pandemic and explored how factors related to COVID-19 may have affected the prevalence of anxiety disorders among the pediatric population.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Childhood anxiety symptoms were assessed at various pediatric practices in Central New Jersey between July 2021 and September 2022. The sample comprised 476 children and adolescents aged 8–17 who participated in the Screen for Child Anxiety Related Disorders (SCARED) questionnaire, administered at their annual well-child visits. Participants included both the child and the caregiver. The anxiety prevalence was compared with prepandemic standards published by the Centers for Disease Control (CDC).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The prevalence of anxiety for children aged 8–17 years (28.3%) was greater than prepandemic levels (7.1%; <i>p</i> < 0.0001). Among children aged 8–11, anxiety increased from 6.6% to 38.1% (<i>p</i> < 0.0001), while for children aged 11–17, anxiety increased from 10.5% to 22.2% (<i>p</i> < 0.0001). Previously diagnosed anxiety was a strong predictor of a high anxiety score on the questionnaire (mean = 28.95) compared with children without a history of anxiety (mean = 17.65; <i>p</i> < 0.001). Furthermore, a disparity was identified in the responses between the child and the caregiver questionnaires (<i>p</i> < 0.0001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study shows that children's anxiety levels increased during the COVID-19 pandemic. Moreover, an inconsistency was found between children self-reporting anxiety and caregivers underreporting their child's anxiety. These findings underscore the need for targeted support for those affected, especially children with a history of anxiety.</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 2","pages":"153-161"},"PeriodicalIF":0.0,"publicationDate":"2024-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140997107","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}
Jamie K. Capal, David M. Ritter, David Neal Franz, Molly Griffith, Kristn Currans, Bridget Kent, E. Martina Bebin, Hope Northrup, Mary Kay Koenig, Tomoyuki Mizuno, Alexander A. Vinks, Stephanie L. Galandi, Wujuan Zhang, Kenneth D.R. Setchell, Kelly M. Kremer, Carlos M. Prada, Hansel M. Greiner, Katherine Holland-Bouley, Paul S. Horn, Darcy A. Krueger
Objective
Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.
Methods
We conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age.
Results
There were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder.
Interpretation
These results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC-STEPS).
{"title":"Preventative treatment of tuberous sclerosis complex with sirolimus: Phase I safety and efficacy results","authors":"Jamie K. Capal, David M. Ritter, David Neal Franz, Molly Griffith, Kristn Currans, Bridget Kent, E. Martina Bebin, Hope Northrup, Mary Kay Koenig, Tomoyuki Mizuno, Alexander A. Vinks, Stephanie L. Galandi, Wujuan Zhang, Kenneth D.R. Setchell, Kelly M. Kremer, Carlos M. Prada, Hansel M. Greiner, Katherine Holland-Bouley, Paul S. Horn, Darcy A. Krueger","doi":"10.1002/cns3.20070","DOIUrl":"10.1002/cns3.20070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Tuberous sclerosis complex (TSC) results from overactivity of the mechanistic target of rapamycin (mTOR). Sirolimus and everolimus are mTOR inhibitors that treat most facets of TSC but are understudied in infants. We sought to understand the safety and potential efficacy of preventative sirolimus in infants with TSC.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a phase 1 clinical trial of sirolimus, treating five patients until 12 months of age. Enrolled infants had to be younger than 6 months of age with no history of seizures and no clinical indication for sirolimus treatment. Adverse events (AEs), tolerability, and blood concentrations of sirolimus measured by tandem mass spectrometry were tracked through 12 months of age, and clinical outcomes (seizure characteristics and developmental profiles) were tracked through 24 months of age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>There were 92 AEs, with 34 possibly, probably, or definitely related to treatment. Of those, only two were grade 3 (both elevated lipids) and all AEs were resolved by the age of 24 months. During the trial, 94% of blood sirolimus trough levels were in the target range (5–15 ng/mL). Treatment was well tolerated, with less than 8% of doses held because of an AE (241 of 2941). Of the five patients, three developed seizures (but were well controlled on medications) at 24 months of age. Of the five patients, four had normal cognitive development for age. One was diagnosed with possible autism spectrum disorder.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These results suggest that sirolimus is both safe and well tolerated by infants with TSC in the first year of life. Additionally, the preliminary work suggests a favorable efficacy profile compared with previous TSC cohorts not exposed to early sirolimus treatment. Results support sirolimus being studied as preventive treatment in TSC, which is now underway in a prospective phase 2 clinical trial (TSC-STEPS).</p>\u0000 </section>\u0000 </div>","PeriodicalId":72232,"journal":{"name":"Annals of the Child Neurology Society","volume":"2 2","pages":"106-119"},"PeriodicalIF":0.0,"publicationDate":"2024-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns3.20070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140672304","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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