Pediatric cerebrovascular disease epidemiology

Pediatric cerebrovascular disease epidemiology

The incidence of pediatric stroke is 1 in 5000, and if hemiplegic cerebral palsy due to vaso-occlusive stroke is included, the number could be as high as 1 in 3000. Additionally, cerebrovascular disease is 1 of the top 10 causes of death in infants younger than 1 year. Finally, 20% to 30% of children with arterial ischemic stroke will have recurrent strokes, even with treatment. Stroke in children differs from stroke in adults. Not only is it rare, but its presentation is subtle—particularly in infants—and even with a focal hemiplegia there is a wide differential diagnosis. Coagulation mechanisms, the arteries, and the neurological systems are all different in children, and each of these plays a large role in stroke. The causes of pediatric stroke do not include atherosclerosis, so a myriad of other risk factors and associations exist and are unique for each age group. The causes of pediatric stroke are poorly understood, and although this is a fertile area of research, clinical trials in the field are lacking. Currently, any treatment guidelines or tools being used to treat children with stroke either come from the field of adult stroke or are based on empirical information.

More than 95% of children with ischemic stroke have an underlying thrombus occluding an artery or a vein, and our understanding of clot pathogenesis in children is increasing. Whereas in adults, platelet clots predominantly form secondary to atherosclerosis, in children and infants there is likely a higher fibrin composition, which may require a different treatment strategy. Although anticoagulation is typically used, it is not known whether anticoagulation is more effective than aspirin. There are also major clinical challenges, the most significant of which is that the diagnosis is not made and the stroke is missed entirely or that the diagnosis is severely delayed and by the time the diagnosis is made, the infarct is much larger 1).


In 1978 A 10-year review of the Mayo Clinic experience with childhood cerebrovascular disease unrelated to birth, intracranial infection, or trauma identified 69 patients (38 with ischemic stroke, and 31 with subarachnoid or intracerebral hemorrhage). Although children with cerebral infarction had better survival, they experienced more residual disability than children with cerebral hemorrhage. The medical records-linkage system for Rochester, Minnesota residents made it possible for the first time to study cerebrovascular disease in a well-defined childhood population. Records from all medical facilities serving this population (average of 15,834 resident children) showed four strokes over 10 years (average annual incidence rate of 2.52 cases per 100,000 per year) 2).


In 2018 a study reported the period prevalence, incidence, and risk factors of pediatric stroke in Taiwan.

All Taiwan inhabitants aged 1 month to 18 years registered in the National Health Insurance Research Database between 2010 and 2011 were enrolled in this study. Factors including age, sex, location, and household income levels were collected. Incidence, period prevalence, mortality rate, and the possible risks were completely evaluated. Outcomes and results: Hemorrhagic stroke has a significantly higher mortality rate than ischemic stroke (27.6% vs. 10.2%, P<0.05). Risk factors or underlying diseases for stroke were identified in 77.8% of the patients and 16.2% had more than one risk factor. The most common risk factors were vascular diseases (26.3%), infection (14.0%), and cardiac disorders (9.1%).

Infants younger than 2 years, boys, and children in lower socioeconomic status have a significantly higher risk of stroke. Hemorrhagic stroke has a significantly higher mortality rate than ischemic stroke. More than half of the children with stroke had underlying diseases and the causes of hemorrhagic stroke are significantly different from ischemic stroke 3).


In 2019 Surmava et al. sought to evaluate in -Ontario, the incidence and characteristics of pediatric stroke and TIA including care gaps and the predictive value of International Classification of Diseases (ICD) codes.

A retrospective chart review was conducted at 147 Ontario pediatric and adult acute care hospitals. Pediatric stroke and TIA cases (age < 18 years) were identified using ICD-10 code searches in the 2010/11 Canadian Institute for Health Information’s Discharge Abstract Database (CIHI-DAD) and National Ambulatory Care Reporting System (NACRS) databases in the Ontario Stroke Audit.

Among 478 potential pediatric strokes and TIA cases identified in the CIHI-DAD and NACRS databases, 163 were confirmed as cases of stroke and TIA during the 1-year study period. The Ontario stroke and TIA incidence rate was 5.9 per 100,000 children (3.3 ischemic, 1.8 hemorrhagic, and 0.8 TIA). The mean age was 6.4 years (16% neonate). Nearly half were not imaged within 24 h of arrival in emergency and only 56% were given antithrombotic treatment. At discharge, 83 out of 121 (69%) required health care services post-discharge. Overall positive predictive value (PPV) of ICD-10 stroke and TIA codes was 31% (range 5-74%) and yield ranged from 2.4 to 29% for acute stroke or TIA event; code I63 achieved maximal PPV and yield.

This population-based study yielded a higher incidence rate than prior North-American studies. Important care gaps exist including delayed diagnosis, lack of expert care, and departure from published treatment guidelines. Variability in ICD PPV and yield underlines the need for prospective data collection and for improving the pediatric stroke and TIA coding processes 4).


It is believed that the incidence in the Hospital Universitario “Dr. Jose Eleuterio Gonzalez,” Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico is higher than it appears.

A study by Garza-Alatorre et al. aimed to assess the incidence and characteristics of pediatric stroke in this university hospital. Likewise, this study seeks to evaluate if a longer symptoms-to-diagnosis time is associated with mortality in patients with ischemic stroke.

Methods: A retrospective study including children with stroke admitted to the UANL University Hospital from January 2013 to December 2016.

Results: A total of 41 patients and 46 stroke episodes were admitted. About 45.7% had an ischemic stroke and 54.3% had a hemorrhagic stroke. Mortality of 24.4% and morbidity of 60.9% were recorded. Regarding ischemic and hemorrhagic stroke, and increased symptoms-to-diagnosis time and a higher mortality were obtained with a relative risk of 2.667 (95% confidence interval [CI]: 1.09-6.524, p = 0.013) and 8.0 (95% CI: 2.18-29.24, p = < 0.0001), respectively. A continuous increase in the incidence rate, ranging from 4.57 to 13.21 per 1,000 admissions comparing the first period (2013) versus the last period (2016), p = 0.02, was found in our center.

Pediatric stroke is a rare disease; however, its incidence shows a continuous increase. More awareness toward pediatric stroke is needed 5).


1)

Bowers KJ, Deveber GA, Ferriero DM, Roach ES, Vexler ZS, Maria BL. Cerebrovascular disease in children: recent advances in diagnosis and management. J Child Neurol. 2011 Sep;26(9):1074-100. doi: 10.1177/0883073811413585. Epub 2011 Jul 21. PMID: 21778188; PMCID: PMC5289387.
2)

Schoenberg BS, Mellinger JF, Schoenberg DG. Cerebrovascular disease in infants and children: a study of incidence, clinical features, and survival. Neurology. 1978 Aug;28(8):763-8. doi: 10.1212/wnl.28.8.763. PMID: 567292.
3)

Chiang KL, Cheng CY. Epidemiology, risk factors and characteristics of pediatric stroke: a nationwide population-based study. QJM. 2018 Jul 1;111(7):445-454. doi: 10.1093/qjmed/hcy066. PMID: 29648667.
4)

Surmava AM, Maclagan LC, Khan F, Kapral MK, Hall RE, deVeber G. Incidence and Current Treatment Gaps in Pediatric Stroke and TIA: An Ontario-Wide Population-Based Study. Neuroepidemiology. 2019;52(3-4):119-127. doi: 10.1159/000493140. Epub 2019 Jan 17. PMID: 30654369.
5)

Garza-Alatorre G, Carrion-Garcia AL, Falcon-Delgado A, Garza-Davila EC, Martinez-Ponce de Leon AR, Botello-Hernandez E. Characteristics of Pediatric Stroke and Association of Delayed Diagnosis with Mortality in a Mexican Tertiary Care Hospital. Neuropediatrics. 2021 Jul 14. doi: 10.1055/s-0041-1731802. Epub ahead of print. PMID: 34261144.

Pediatric traumatic brain injury guidelines

Pediatric traumatic brain injury guidelines

see Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition

In a systematic review and guideline appraisal for pediatric clinical practice guidelines (CPGs) concerning the acute management of Pediatric Traumatic Brain Injury. Targeted guideline creation specific to the pediatric population has the potential to improve the quality of acute TBI clinical practice guidelines (CPGs).

Furthermore, it is crucial to address the applicability of a guideline to translate the CPG from a published manuscript into clinically relevant local practice tools and for resource limited practice settings 1).

Guidelines for Diagnosing and Managing Pediatric Concussion

Guidelines.


Thromboprophylaxis in Traumatic brain injury:

Low-molecular-weight heparin (LMWH) prophylaxis in pediatric traumatic brain injury appears to be more effective than unfractionated heparin (UH) in preventing venous thromboembolism (VTE). Large, multicenter prospective studies are warranted to confirm the superiority of LMWH over UH in pediatric patients with traumatic brain injury. Moreover, outcomes of VTE prophylaxis in the very young remain understudied; therefore, dedicated studies to evaluate this population are needed 2).


1)

Appenteng R, Nelp T, Abdelgadir J, Weledji N, Haglund M, Smith E, Obiga O, Sakita FM, Miguel EA, Vissoci CM, Rice H, Vissoci JRN, Staton C. A systematic review and quality analysis of pediatric traumatic brain injury clinical practice guidelines. PLoS One. 2018 Aug 2;13(8):e0201550. doi: 10.1371/journal.pone.0201550. eCollection 2018. PubMed PMID: 30071052; PubMed Central PMCID: PMC6072093.
2)

van Erp IA, Gaitanidis A, El Moheb M, Kaafarani HMA, Saillant N, Duhaime AC, Mendoza AE. Low-molecular-weight heparin versus unfractionated heparin in pediatric traumatic brain injury. J Neurosurg Pediatr. 2021 Feb 12:1-6. doi: 10.3171/2020.9.PEDS20615. Epub ahead of print. PMID: 33578391.

Pediatric Low-Grade Glioma Classification

Pediatric Low-Grade Gliomas (PLGGs) display heterogeneity regarding morphology, genomic drivers and clinical outcomes.

They constitute the largest, yet clinically and (molecular-) a histologically heterogeneous group of pediatric brain tumors of WHO grade I and II occurring throughout all pediatric age groups and at all central nervous system (CNS) sites. The tumors are characterized by a slow growth rate and may show periods of growth arrest 1).

Pediatric low-grade gliomas were shown to be characterized by an array of distinct molecular aberrations. The cIMPACT-4 consensus proposed pediatric low-grade gliomas of the diffuse type to be characterized by distinct molecular changes rather than distinct histological features.

Fukuoka et al. described a small series of pediatric oligodendroglioma-like tumors with BRAF V600E mutations. Interestingly, they exhibited molecular changes usually associated with adult high-grade gliomas: chromosome instability, chromosome 7 gains, and chromosome 10 loss, but had an indolent natural history 2) 3).

Genetic abnormalities

Mobark et al. profiled a targeted panel of cancer-related genes in 37 Saudi Arabian patients with pLGGs to identify genetic abnormalities that can inform prognostic and therapeutic decision-making. THey detected genetic alterations (GAs) in 97% (36/37) of cases, averaging 2.51 single nucleotide variations (SNVs) and 0.91 gene fusions per patient. The KIAA1549-BRAF fusion was the most common alteration (21/37 patients) followed by AFAP1-NTRK2 (2/37) and TBLXR-PI3KCA (2/37) fusions that were observed at much lower frequencies. The most frequently mutated) genes were NOTCH1-3 (7/37), ATM (4/37), RAD51C (3/37), RNF43 (3/37), SLX4 (3/37) and NF1 (3/37). Interestingly, they identified a GOPCROS1 fusion in an 8-year-old patient whose tumor lacked BRAF alterations and histologically classified as low-grade glioma. The patient underwent gross total resection (GTR). The patient is currently disease-free. To the author’s knowledge, this is the first report of GOPC-ROS1 fusion in PLGG. Taken together, they revealed the genetic characteristics of pLGG patients can enhance diagnostics and therapeutic decisions. In addition, we identified a GOPC-ROS1 fusion that may be a biomarker for pLGG 4).


Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway.

This has led to PLGG clinical trials utilizing RAF– and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways. Although ATP-competitive, first-generation RAF inhibitors (vemurafenib/PLX4720, RAFi) cause paradoxical activation of the MAPK pathway in BRAF-fusion tumors, inhibition can be achieved with ‘paradox breaker’ RAFi, such as PLX8394.

Jain et al. report that, unlike BRAF fusions, CRAF fusions are unresponsive to both generations of RAFi, vemurafenib and PLX8394, highlighting a distinct responsiveness of CRAF fusions to clinically relevant RAFi. Whereas PLX8394 decreased BRAF-fusion dimerization, CRAF-fusion dimerization is unaffected primarily because of robust protein-protein interactions mediated by the N-terminal non-kinase fusion partner, such as QKI. The pan-RAF dimer inhibitor, LY3009120, could suppress CRAF-fusion oncogenicity by inhibiting dimer-mediated signaling. In addition, as CRAF fusions activate both the MAPK and PI3K/mTOR signaling pathways, we identify combinatorial inhibition of the MAPK/mTOR pathway as a potential therapeutic strategy for CRAF-fusion-driven tumors. Overall, we define a mechanistic distinction between PLGG-associated BRAF- and CRAF/RAF1 fusions in response to RAFi, highlighting the importance of molecularly classifying PLGG patients for targeted therapy. Furthermore, this study uncovers an important contribution of the non-kinase fusion partner to oncogenesis and potential therapeutic strategies against PLGG-associated CRAF fusions and possibly pan-cancer CRAF fusions 5).

References

1)

Gnekow AK, Kandels D, Tilburg CV, Azizi AA, Opocher E, Stokland T, Driever PH, Meeteren AYNSV, Thomale UW, Schuhmann MU, Czech T, Goodden JR, Warmuth-Metz M, Bison B, Avula S, Kortmann RD, Timmermann B, Pietsch T, Witt O. SIOP-E-BTG and GPOH Guidelines for Diagnosis and Treatment of Children and Adolescents with Low Grade Glioma. Klin Padiatr. 2019 May;231(3):107-135. doi: 10.1055/a-0889-8256. Epub 2019 May 20. PubMed PMID: 31108561.
2)

Yang RR, Li KK, Liu APY, Chen H, Chung NY, Chan AKY, Li F, Tat-Ming Chan D, Mao Y, Shi ZF, Ng HK. Low-grade BRAF V600E mutant oligodendroglioma-like tumors of children may show EGFR and MET amplification. Brain Pathol. 2020 Oct 8. doi: 10.1111/bpa.12904. Epub ahead of print. PMID: 33032379.
3)

Fukuoka K, Mamatjan Y, Ryall S, Komosa M, Bennett J, Zapotocky M, Keith J, Myrehaug S, Hazrati LN, Aldape K, Laperriere N, Bouffet E, Tabori U, Hawkins C. BRAF V600E mutant oligodendroglioma-like tumors with chromosomal instability in adolescents and young adults. Brain Pathol. 2020 May;30(3):515-523. doi: 10.1111/bpa.12799. Epub 2019 Nov 10. PMID: 31630459.
4)

Mobark NA, Alharbi M, Alhabeeb L, AlMubarak L, Alaljelaify R, AlSaeed M, Almutairi A, Alqubaishi F, Ahmad M, Al-Banyan A, Alotabi FE, Barakeh D, AlZahrani M, Al-Khalidi H, Ajlan A, Ramkissoon LA, Ramkissoon SH, Abedalthagafi M. Clinical management and genomic profiling of pediatric low-grade gliomas in Saudi Arabia. PLoS One. 2020 Jan 29;15(1):e0228356. doi: 10.1371/journal.pone.0228356. eCollection 2020. PubMed PMID: 31995621.
5)

Jain P, Fierst TM, Han HJ, Smith TE, Vakil A, Storm PJ, Resnick AC, Waanders AJ. CRAF gene fusions in pediatric low-grade gliomas define a distinct drug response based on dimerization profiles. Oncogene. 2017 Aug 14. doi: 10.1038/onc.2017.276. [Epub ahead of print] PubMed PMID: 28806393.
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