EDITORIALS
September 2015 population, the ASD symptoms in patients with NF1 did not appear to exhibit a strong male predilection. Based upon these 2 disparate studies, it is clear that we are entering an era in which ethnic, epigenetic, and genotypic information may provide some guidance in how we approach management paradigms for patients with any number of genetic conditions, including NF1. If we are able to identify which of our patients with NF1 are at highest risk for comorbid conditions, such as pediatric brain tumor/ONGs, ASD, or ADHD, we may be able to take advantage of aggressive screening measures, earlier diagnosis, and intensive interventions for those most likely to be impacted. Future avenues of investigation should include possible genotype-phenotype association studies looking at mutation risk profiles, as well as developing personalized screening strategies that target the highest risk patients and modifying current screening recommendations as well for those that are perhaps at lowest risk for specific medical complications. This approach may also be useful to identify those individuals at greatest risk for additional serious complications such as malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, or spinal cord neurofibromas. Identifying other genetic and epigenetic influences that affect neurofibromin function and expression may also provide a foundation to understand better the pathologic processes in NF1 and could lead to targeted treatments and interventions to mitigate or even eliminate the effects of a neurofibromin mutation. n Beth A. Pletcher, MD, FAAP, FACMG Division of Clinical Genetics Department of Pediatrics Caroline Hayes-Rosen, MD, FAAN Department of Neurology and Neurosciences The Neurofibromatosis Center of New Jersey Newark, New Jersey Reprint requests: Beth A. Pletcher, MD, FAAP, FACMG, Division of Clinical Genetics, Department of Pediatrics, The Neurofibromatosis Center of New
Jersey, 90 Bergen St, Suite 5400 Newark, NJ 07103. E-mail: pletchba@njms. rutgers.edu
References 1. Listernick R, Ferner RE, Lui GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007;61:189-98. 2. Abadin SS, Zoellner NL, Schaeffer M, Porcelli B, Gutmann DH, Johnson K. Racial/ethnic differences in pediatric brain tumor diagnoses in patients with neurofibromatosis type 1. J Pediatr 2015;167:613-20. 3. Caen S, Cassiman C, Legius E, Casteels I. Comparative study of the ophthalmological examinations in neurofibromatosis type 1. Proposal for a new screening algorithm. Eur J Paediatr Neurol 2015;19:415-22. 4. Ars E, Kruyer H, Morell M, Pros E, Serra E, Ravella A, et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet 2003;40:e82. 5. Sharif S, Upadhyaya M, Ferner R, Majounie E, Shenton A, Baser M, et al. A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotypephenotype correlations. J Med Genet 2011;48:256-60. 6. North K, Joy P, Yuille D, Cocks N, Hutchins P. Cognitive function and academic performance in children with neurofibromatosis type 1. Dev Med Child Neurol 1995;37:427-36. 7. Lehtonen A, Garg S, Roberts SA, Trump D, Evans DG, Green J, et al. Cognition in children with neurofibromatosis type 1: data from a population-based study. Dev Med Child Neurol 2015;57:645-51. 8. Mautner V-F, Kluwe L, Thakker SD, Leark RA. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol 2002;44:164-70. 9. Barton B, North K. Social skills of children with neurofibromatosis type 1. Dev Child Neurol 2004;46:553-63. 10. Walsh KS, Velez JI, Kardel PG, Imas DM, Muenke M, Packer RJ, et al. Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol 2012;55:131-8. 11. Garg S, Lehtonen A, Huson SM, Emsley R, Trump D, Evans DG, et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol 2013;55:139-45. 12. Plasschaert E, Descheemaeker M-J, Van Eylen L, Noens I, Steyaert J, Legius E. Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet 2014;168B:72-80. 13. Constantino JN, Zhang Y, Holzhauer K, Sant S, Long K, Vallorani A, et al. Distribution and within-family specificity of quantitative autistic traits in patients with neurofibromatosis 1. J Pediatr 2015;167:621-6.
What is the Big Deal about the BIG Score?
I
0.89 and outperformed all other trauma scores. This study n this issue of The Journal, Davis et al report the progof pediatric blunt trauma in Canada reports an even nostic accuracy of the pediatric trauma BIG score for higher ROC-area under the curve of 0.95 (0.93-0.98). critically injured children from a level 1 trauma center This is more accurate compared with the injury severity in Ontario, Canada.1 The score was originally developed score, which simply evaluates the degree of anatomic based on a unique population of children with predomiinjury and takes significant time and nantly blast and penetrating trauma in See related article, p 593 Iraq and Afghanistan and later validated on a blunt trauma population of children in Europe.2 Interestingly, the original manuscript reported a receiver The view(s) expressed herein are those of the author(s) and do not reflect the official operator characteristic (ROC)-area under the curve of policy or position of Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army and Department of Defense, or the US Government. The authors declare no conflicts of interest.
ROC
Receiver operator characteristic
0022-3476//$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpeds.2015.06.039
513
THE JOURNAL OF PEDIATRICS
www.jpeds.com
training to calculate retrospectively. This validation of the BIG score examined 621 pediatric patients with blunt trauma from 2001 to 2012. Their ROC analysis indicated an optimal score cutoff of 16, which corresponds to a negative predictive value of 99% for mortality. The plot of mortality and BIG score also indicates that those with a score less than 10 typically survived, whereas a score greater than 40 was almost uniformly fatal. As the authors note, the power of this score may lie in that fact that it addresses the key features that have been associated previously with trauma outcomes: base deficit, an indicator of perfusion; international normalized ratio, an indicator of coagulopathy; and Glasgow coma score, one measure of the degree of traumatic brain injury, as well as cerebral perfusion. This study did not compare the score with the Pediatric Risk of Mortality III or Pediatric Index of Mortality 2, though these were derived and validated on all pediatric patients, not just trauma patients.3,4 The authors discuss several other lesser known pediatric trauma scores, though unfortunately it was outside the scope of this manuscript to compare these with the BIG score. Part of the difficulty in that analysis is that these other scoring systems have multiple variables, some of which need to be normalized to age. The more variables a score requires, the more likely there will be missing variables in a large database analysis. The clear advantage of the BIG score is its accuracy, simplicity, and ability to obtain all variables with point of care testing at admission. With point of care testing, the international normalized ratio and base deficit can be determined in approximately 2 minutes. Beyond the score’s prognostic value, there are 2 potentially significant applications: patient selection for trials and trauma center outcome benchmarking. The ability to rapidly stratify patients at admission is essential for quickly enrolling patients into a trial for a particular resuscitation strategy. Although head injury is the main cause of death in pediatric trauma, and often is independent of treatment, the main cause of preventable death in trauma is hemorrhage.5 The authors did show that the BIG score remained predictive of death independent from head injuries and also noted that there was a clear score difference in those who received transfusions (BIG mean 17) vs those who did not (mean 8). Future study is needed to determine if there is a BIG score optimal cutoff for those patients at risk of a massive transfusion as this could help alert blood bank resources as soon as possible. A certain score could also be utilized to determine if pediatric patients would benefit from damage control resuscitation6 or the use of an antifibrinolytic,7 as these strategies have not been prospectively tested in a pediatric population.
514
Vol. 167, No. 3 Given that this score can be obtained at admission, its prognostic value should be less affected by the care delivered in the first 12-24 hours, compared with scores which are calculated later in a patient’s course, which may reflect the quality of care. The score may have value comparing and benchmarking outcomes both within and between trauma centers. There may also be some value utilizing this score to help match patients in propensity studies comparing treatment strategies prior to embarking on a large prospective randomized trial. Davis et al have provided an essential next step validating the accuracy of the BIG score. As the authors suggest, prospective multicenter analyses are needed to more thoroughly validate its usefulness for both clinical and research applications. Pediatric trauma and neurocritical care programs will benefit from a simple, rapidly available, physiologically relevant, and accurate tool to assist with prognosis, benchmarking, and trial design. Big improvements in care might be possible with the application of the BIG score. n Matthew A. Borgman, MD San Antonio Military Medical Center Ft. Sam Houston, Texas Philip C. Spinella, MD Washington University in St. Louis St. Louis, Missouri Reprint requests: Matthew A. Borgman, MD, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Ft. Sam Houston, TX 78234. E-mail: [email protected]
References 1. Davis AL, Wales PW, Malik T, Stephens D, Razik F, Schuh S. The BIG score and prediction of mortality in pediatric blunt trauma. J Pediatr 2015;167:593-8. 2. Borgman MA, Maegele M, Wade CE, Blackbourne LH, Spinella PC. Pediatric trauma BIG score: predicting mortality in children after military and civilian trauma. Pediatrics 2011;127:e892-7. 3. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med 1996;24:743-52. 4. Slater A, Shann F, Pearson G, Paediatric Index of Mortality Study Group. PIM2: a revised version of the Paediatric Index of Mortality. Intensive Care Med 2003;29:278-85. 5. Christiaans SC, Duhachek-Stapelman AL, Russell RT, Lisco SJ, Kerby JD, Pittet JF. Coagulopathy after severe pediatric trauma. Shock 2014;41: 476-90. 6. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007;62:307-10. 7. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial. Lancet 2010;376:23-32.
September 2015 population, the ASD symptoms in patients with NF1 did not appear to exhibit a strong male predilection. Based upon these 2 disparate studies, it is clear that we are entering an era in which ethnic, epigenetic, and genotypic information may provide some guidance in how we approach management paradigms for patients with any number of genetic conditions, including NF1. If we are able to identify which of our patients with NF1 are at highest risk for comorbid conditions, such as pediatric brain tumor/ONGs, ASD, or ADHD, we may be able to take advantage of aggressive screening measures, earlier diagnosis, and intensive interventions for those most likely to be impacted. Future avenues of investigation should include possible genotype-phenotype association studies looking at mutation risk profiles, as well as developing personalized screening strategies that target the highest risk patients and modifying current screening recommendations as well for those that are perhaps at lowest risk for specific medical complications. This approach may also be useful to identify those individuals at greatest risk for additional serious complications such as malignant peripheral nerve sheath tumors, gastrointestinal stromal tumors, or spinal cord neurofibromas. Identifying other genetic and epigenetic influences that affect neurofibromin function and expression may also provide a foundation to understand better the pathologic processes in NF1 and could lead to targeted treatments and interventions to mitigate or even eliminate the effects of a neurofibromin mutation. n Beth A. Pletcher, MD, FAAP, FACMG Division of Clinical Genetics Department of Pediatrics Caroline Hayes-Rosen, MD, FAAN Department of Neurology and Neurosciences The Neurofibromatosis Center of New Jersey Newark, New Jersey Reprint requests: Beth A. Pletcher, MD, FAAP, FACMG, Division of Clinical Genetics, Department of Pediatrics, The Neurofibromatosis Center of New
Jersey, 90 Bergen St, Suite 5400 Newark, NJ 07103. E-mail: pletchba@njms. rutgers.edu
References 1. Listernick R, Ferner RE, Lui GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol 2007;61:189-98. 2. Abadin SS, Zoellner NL, Schaeffer M, Porcelli B, Gutmann DH, Johnson K. Racial/ethnic differences in pediatric brain tumor diagnoses in patients with neurofibromatosis type 1. J Pediatr 2015;167:613-20. 3. Caen S, Cassiman C, Legius E, Casteels I. Comparative study of the ophthalmological examinations in neurofibromatosis type 1. Proposal for a new screening algorithm. Eur J Paediatr Neurol 2015;19:415-22. 4. Ars E, Kruyer H, Morell M, Pros E, Serra E, Ravella A, et al. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet 2003;40:e82. 5. Sharif S, Upadhyaya M, Ferner R, Majounie E, Shenton A, Baser M, et al. A molecular analysis of individuals with neurofibromatosis type 1 (NF1) and optic pathway gliomas (OPGs), and an assessment of genotypephenotype correlations. J Med Genet 2011;48:256-60. 6. North K, Joy P, Yuille D, Cocks N, Hutchins P. Cognitive function and academic performance in children with neurofibromatosis type 1. Dev Med Child Neurol 1995;37:427-36. 7. Lehtonen A, Garg S, Roberts SA, Trump D, Evans DG, Green J, et al. Cognition in children with neurofibromatosis type 1: data from a population-based study. Dev Med Child Neurol 2015;57:645-51. 8. Mautner V-F, Kluwe L, Thakker SD, Leark RA. Treatment of ADHD in neurofibromatosis type 1. Dev Med Child Neurol 2002;44:164-70. 9. Barton B, North K. Social skills of children with neurofibromatosis type 1. Dev Child Neurol 2004;46:553-63. 10. Walsh KS, Velez JI, Kardel PG, Imas DM, Muenke M, Packer RJ, et al. Symptomatology of autism spectrum disorder in a population with neurofibromatosis type 1. Dev Med Child Neurol 2012;55:131-8. 11. Garg S, Lehtonen A, Huson SM, Emsley R, Trump D, Evans DG, et al. Autism and other psychiatric comorbidity in neurofibromatosis type 1: evidence from a population-based study. Dev Med Child Neurol 2013;55:139-45. 12. Plasschaert E, Descheemaeker M-J, Van Eylen L, Noens I, Steyaert J, Legius E. Prevalence of autism spectrum disorder symptoms in children with neurofibromatosis type 1. Am J Med Genet 2014;168B:72-80. 13. Constantino JN, Zhang Y, Holzhauer K, Sant S, Long K, Vallorani A, et al. Distribution and within-family specificity of quantitative autistic traits in patients with neurofibromatosis 1. J Pediatr 2015;167:621-6.
What is the Big Deal about the BIG Score?
I
0.89 and outperformed all other trauma scores. This study n this issue of The Journal, Davis et al report the progof pediatric blunt trauma in Canada reports an even nostic accuracy of the pediatric trauma BIG score for higher ROC-area under the curve of 0.95 (0.93-0.98). critically injured children from a level 1 trauma center This is more accurate compared with the injury severity in Ontario, Canada.1 The score was originally developed score, which simply evaluates the degree of anatomic based on a unique population of children with predomiinjury and takes significant time and nantly blast and penetrating trauma in See related article, p 593 Iraq and Afghanistan and later validated on a blunt trauma population of children in Europe.2 Interestingly, the original manuscript reported a receiver The view(s) expressed herein are those of the author(s) and do not reflect the official operator characteristic (ROC)-area under the curve of policy or position of Brooke Army Medical Center, the US Army Medical Department, the US Army Office of the Surgeon General, the Department of the Army and Department of Defense, or the US Government. The authors declare no conflicts of interest.
ROC
Receiver operator characteristic
0022-3476//$ - see front matter. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jpeds.2015.06.039
513
THE JOURNAL OF PEDIATRICS
www.jpeds.com
training to calculate retrospectively. This validation of the BIG score examined 621 pediatric patients with blunt trauma from 2001 to 2012. Their ROC analysis indicated an optimal score cutoff of 16, which corresponds to a negative predictive value of 99% for mortality. The plot of mortality and BIG score also indicates that those with a score less than 10 typically survived, whereas a score greater than 40 was almost uniformly fatal. As the authors note, the power of this score may lie in that fact that it addresses the key features that have been associated previously with trauma outcomes: base deficit, an indicator of perfusion; international normalized ratio, an indicator of coagulopathy; and Glasgow coma score, one measure of the degree of traumatic brain injury, as well as cerebral perfusion. This study did not compare the score with the Pediatric Risk of Mortality III or Pediatric Index of Mortality 2, though these were derived and validated on all pediatric patients, not just trauma patients.3,4 The authors discuss several other lesser known pediatric trauma scores, though unfortunately it was outside the scope of this manuscript to compare these with the BIG score. Part of the difficulty in that analysis is that these other scoring systems have multiple variables, some of which need to be normalized to age. The more variables a score requires, the more likely there will be missing variables in a large database analysis. The clear advantage of the BIG score is its accuracy, simplicity, and ability to obtain all variables with point of care testing at admission. With point of care testing, the international normalized ratio and base deficit can be determined in approximately 2 minutes. Beyond the score’s prognostic value, there are 2 potentially significant applications: patient selection for trials and trauma center outcome benchmarking. The ability to rapidly stratify patients at admission is essential for quickly enrolling patients into a trial for a particular resuscitation strategy. Although head injury is the main cause of death in pediatric trauma, and often is independent of treatment, the main cause of preventable death in trauma is hemorrhage.5 The authors did show that the BIG score remained predictive of death independent from head injuries and also noted that there was a clear score difference in those who received transfusions (BIG mean 17) vs those who did not (mean 8). Future study is needed to determine if there is a BIG score optimal cutoff for those patients at risk of a massive transfusion as this could help alert blood bank resources as soon as possible. A certain score could also be utilized to determine if pediatric patients would benefit from damage control resuscitation6 or the use of an antifibrinolytic,7 as these strategies have not been prospectively tested in a pediatric population.
514
Vol. 167, No. 3 Given that this score can be obtained at admission, its prognostic value should be less affected by the care delivered in the first 12-24 hours, compared with scores which are calculated later in a patient’s course, which may reflect the quality of care. The score may have value comparing and benchmarking outcomes both within and between trauma centers. There may also be some value utilizing this score to help match patients in propensity studies comparing treatment strategies prior to embarking on a large prospective randomized trial. Davis et al have provided an essential next step validating the accuracy of the BIG score. As the authors suggest, prospective multicenter analyses are needed to more thoroughly validate its usefulness for both clinical and research applications. Pediatric trauma and neurocritical care programs will benefit from a simple, rapidly available, physiologically relevant, and accurate tool to assist with prognosis, benchmarking, and trial design. Big improvements in care might be possible with the application of the BIG score. n Matthew A. Borgman, MD San Antonio Military Medical Center Ft. Sam Houston, Texas Philip C. Spinella, MD Washington University in St. Louis St. Louis, Missouri Reprint requests: Matthew A. Borgman, MD, San Antonio Military Medical Center, 3551 Roger Brooke Drive, Ft. Sam Houston, TX 78234. E-mail: [email protected]
References 1. Davis AL, Wales PW, Malik T, Stephens D, Razik F, Schuh S. The BIG score and prediction of mortality in pediatric blunt trauma. J Pediatr 2015;167:593-8. 2. Borgman MA, Maegele M, Wade CE, Blackbourne LH, Spinella PC. Pediatric trauma BIG score: predicting mortality in children after military and civilian trauma. Pediatrics 2011;127:e892-7. 3. Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated Pediatric Risk of Mortality score. Crit Care Med 1996;24:743-52. 4. Slater A, Shann F, Pearson G, Paediatric Index of Mortality Study Group. PIM2: a revised version of the Paediatric Index of Mortality. Intensive Care Med 2003;29:278-85. 5. Christiaans SC, Duhachek-Stapelman AL, Russell RT, Lisco SJ, Kerby JD, Pittet JF. Coagulopathy after severe pediatric trauma. Shock 2014;41: 476-90. 6. Holcomb JB, Jenkins D, Rhee P, Johannigman J, Mahoney P, Mehta S, et al. Damage control resuscitation: directly addressing the early coagulopathy of trauma. J Trauma 2007;62:307-10. 7. CRASH-2 trial collaborators, Shakur H, Roberts I, Bautista R, Caballero J, Coats T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant hemorrhage (CRASH-2): a randomized, placebo-controlled trial. Lancet 2010;376:23-32.
