Publications by authors named "Heather J Fullerton"

101 Publications

A Web-based System to Assist With Etiology Differential Diagnosis in Children With Arterial Ischemic Stroke.

Top Magn Reson Imaging 2021 Oct;30(5):253-257

Department of Radiology, Neuroradiology Section, Stanford University, Stanford, CA.

Background And Purpose: The diagnosis of childhood arteriopathy is complex. We present a Web-based, evidence-backed classification system to return the most likely cause(s) of a pediatric arterial ischemic stroke. This tool incorporates a decision-making algorithm that considers a patient's clinical and imaging features before returning a differential diagnosis, including the likelihood of various arteriopathy subtypes.

Methods: The Vascular Effects of Infection in Pediatric Stroke study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). Previously, a central panel of experts classified the stroke etiology. To create this tool, we used the 174 patients with definite arteriopathy and spontaneous cardioembolic stroke as the "derivation cohort" and the 34 with "possible" arteriopathy as the "test cohort." Using logistic regression models of clinical and imaging characteristics associated with each arteriopathy subtype in the derivation cohort, we built a decision framework that we integrated into a Web interface specifically designed to create a probabilistic differential diagnosis. We applied the Web-based tool to the "test cohort."

Results: The differential diagnosis returned by our tool was in complete agreement with the experts' opinions in 20.6% of patients. We observed a partial agreement in 41.2% of patients and an overlap in 29.4% of patients. The tool disagreed with the experts on the diagnoses of 3 patients (8.8%).

Conclusions: Our tool yielded an overlapping differential diagnosis in most patients that defied definitive classification by experts. Although it needs to be validated in an independent cohort, it helps facilitate high-quality, and timely diagnoses of arteriopathy in pediatric patients.
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http://dx.doi.org/10.1097/RMR.0000000000000285DOI Listing
October 2021

Factors associated with seizures at initial presentation in pediatric patients with cerebral arteriovenous malformations.

J Neurosurg Pediatr 2021 Sep 24:1-6. Epub 2021 Sep 24.

1Department of Neurological Surgery, University of California San Francisco, San Francisco.

Objective: Children with cerebral arteriovenous malformations (AVMs) can present with seizures, potentially increasing morbidity and impacting clinical management. However, the factors that lead to seizures as a presenting sign are not well defined. While AVM-related seizures have been described in case series, most studies have focused on adults and have included patients who developed seizures after an AVM rupture. To address this, the authors sought to analyze demographic and morphological characteristics of AVMs in a large cohort of children.

Methods: The demographic, clinical, and AVM morphological characteristics of 189 pediatric patients from a single-center database were studied. Univariate and multivariate logistic regression models were used to test the effect of these characteristics on seizures as an initial presenting symptom in patients with unruptured brain AVMs.

Results: Overall, 28 of 189 patients initially presented with seizures (14.8%). By univariate comparison, frontal lobe location (p = 0.02), larger AVM size (p = 0.003), older patient age (p = 0.04), and the Supplemented Spetzler-Martin (Supp-SM) grade (0.0006) were associated with seizure presentation. Multivariate analysis confirmed an independent effect of frontal lobe AVM location and higher Supp-SM grade. All patients presenting with seizures had AVMs in the cortex or subcortical white matter.

Conclusions: While children and adults share some risk factors for seizure presentation, their risk factor profiles do not entirely overlap. Pediatric patients with cortical AVMs in the frontal lobe were more likely to present with seizures. Additionally, the Supp-SM grade was highly associated with seizure presentation. Future clinical research should focus on the effect of therapeutic interventions targeting AVMs on seizure control in these patients.
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http://dx.doi.org/10.3171/2021.6.PEDS21126DOI Listing
September 2021

Stroke in Children.

Stroke 2021 10 2;52(10):3388-3390. Epub 2021 Sep 2.

Departments of Neurology and Pediatrics, University of California, San Francisco (H.J.F.).

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http://dx.doi.org/10.1161/STROKEAHA.121.033967DOI Listing
October 2021

Pediatric moyamoya MRI score: an imaging-based scale to predict outcomes in surgically treated pediatric patients with moyamoya.

Neurosurg Focus 2021 09;51(3):E8

2Department of Radiology and Biomedical Imaging, University of California, San Francisco.

Objective: Moyamoya is a progressive arteriopathy that predisposes patients to stroke due to stenosis of the intracranial internal carotid arteries and their proximal branches. Despite the morbidity caused by this condition, the ability to accurately predict prognosis for individual patients remains challenging. The goal of this study was to develop a systematic scoring method based on parenchymal findings on preoperative brain MRI to predict long-term outcomes for surgically treated pediatric patients with moyamoya.

Methods: A retrospective surgical cohort of pediatric patients (≤ 18 years of age at the time of the initial surgery) with moyamoya from a single center were studied. Radiological variables with existing correlations between outcomes in moyamoya or other vascular diseases were chosen to score preoperative MRI based on easily defined parenchymal findings that could be rapidly assessed and used to make a numeric score. Calculated scores were correlated with clinical outcome measures using the Pearson correlation coefficient and area under the receiver operating characteristic curve (AUROC).

Results: A total of 35 children with moyamoya disease or moyamoya syndrome were included in the study, with a median follow-up time of 2.6 years from the time of surgery. The pediatric moyamoya MRI score (PMMS) consists of ischemic changes (0-2; 0 = none, 1 = focal, 2 = diffuse), encephalomalacia (0-2; 0 = none, 1 = focal, 2 = diffuse), and hemorrhage (0-1; 0 = not present, 1 = present). PMMSs were highly correlated with pediatric modified Rankin Scale scores at the last follow-up (r = 0.7, 95% CI 0.44-0.84; p < 0.001) as a six-point scale, and when dichotomized (AUROC = 0.85).

Conclusions: The PMMS was found to be a simple tool based on preoperative MRI data that could be quickly and easily calculated and correlated with disability. This scoring method may aid future development of predictive models of outcomes for children with moyamoya disease and moyamoya syndrome.
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http://dx.doi.org/10.3171/2021.6.FOCUS21283DOI Listing
September 2021

Current treatment for childhood arterial ischaemic stroke.

Lancet Child Adolesc Health 2021 Nov 29;5(11):825-836. Epub 2021 Jul 29.

Department of Radiology, University Hospital Munich, LMU Munich, Munich, Germany. Electronic address:

Paediatric arterial ischaemic stroke is an important cause of neurological morbidity in children, with consequences including motor disorders, intellectual impairment, and epilepsy. The causes of paediatric arterial ischaemic stroke are unique compared with those associated with stroke in adulthood. The past decade has seen substantial advances in paediatric stroke research and clinical care, but many unanswered questions and controversies remain. Shortage of prospective evidence for the use of recanalisation therapies in patients with paediatric stroke has resulted in little standardisation of disease management. Substantial time delays in diagnosis and treatment continue to challenge best possible care. In this Review, we highlight on some of the most pressing and productive aspects of research in the treatment of arterial ischaemic stroke in children, including epidemiology and cause, rehabilitation, secondary stroke prevention, and treatment updates focusing on advances in hyperacute therapies such as intravenous thrombolysis, mechanical thrombectomy, and critical care. Finally, we provide a future perspective for improving outcomes and quality of life for affected children and their families.
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http://dx.doi.org/10.1016/S2352-4642(21)00167-XDOI Listing
November 2021

Common Features Between Stroke Following Varicella in Children and Stroke Following Herpes Zoster in Adults : Varicella-Zoster Virus in Trigeminal Ganglion.

Curr Top Microbiol Immunol 2021 Jul 6. Epub 2021 Jul 6.

Division of Child Neurology and Pediatric Brain Center, Department of Neurology, University of California San Francisco, San Francisco, California, USA.

The cerebral arteries are innervated by afferent fibers from the trigeminal ganglia. Varicella-zoster virus (VZV) frequently resides in the trigeminal ganglion. Reports of arterial ischemic stroke due to VZV cerebral vasculopathy in adults after herpes zoster have been described for decades. Reports of arterial ischemic stroke due to post-varicella cerebral arteriopathy in children have also been described for decades. One rationale for this review has been post-licensure studies that have shown an apparent protective effect from stroke in both adults who have received live zoster vaccine and children who have received live varicella vaccine. In this review, we define common features between stroke following varicella in children and stroke following herpes zoster in adults. The trigeminal ganglion and to a lesser extent the superior cervical ganglion are central to the stroke pathogenesis pathway because afferent fibers from these two ganglia provide the circuitry by which the virus can travel to the anterior and posterior circulations of the brain. Based on studies in pseudorabies virus (PRV) models, it is likely that VZV is carried to the cerebral arteries on a kinesin motor via gE, gI and the homolog of PRV US9. The gE product is an essential VZV protein.
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http://dx.doi.org/10.1007/82_2021_236DOI Listing
July 2021

Clinical outcomes after revascularization for pediatric moyamoya disease and syndrome: A single-center series.

J Clin Neurosci 2020 Sep 19;79:137-143. Epub 2020 Aug 19.

Departments of Neurology and Pediatrics, University of California, San Francisco, CA, USA. Electronic address:

Moyamoya is a progressive cerebrovascular arteriopathy that affects children of any age. The goal of this study was to determine imaging and clinical outcomes as well as complication rates in a pediatric cohort undergoing either a combined direct/indirect or indirect-only revascularization approach. Patients with moyamoya disease or syndrome ≤ 18 years of age at the time of initial surgery were identified, and clinical data were collected retrospectively. Over a 12-year period, 26 patients underwent revascularization procedures on 49 hemispheres with a median follow-up of 2.6 years from surgery. Median age at surgery was 7.3 years (range 1.4-18.0 years). Thirty-three hemispheres (67.3%) underwent combined revascularization with a direct bypass and encephalomyosynangiosis, and sixteen hemispheres (32.7%) underwent indirect-only revascularization. The rate of 30-day perioperative complication was 10.2%, and the rate of postoperative clinical stroke by end of follow-up was 10.2% by hemisphere. There was a 5.7% rate of intraoperative bypass failure requiring conversion to an indirect revascularization approach. On follow-up imaging, 96.9% of direct bypasses remained patent. On multivariate analysis, higher preoperative Pediatric Stroke Outcome Measure (PSOM) scores were associated with lower rates of good clinical outcome on follow-up (unit OR 0.03; p = 0.03). Patients with age < 5.4 years had lower rates of good clinical outcome on follow-up. In this North American cohort, both combined direct/indirect and indirect only revascularization techniques were feasible. However, younger children < 5.4 years of age have worse outcomes than older children, similar to east Asian cohorts.
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http://dx.doi.org/10.1016/j.jocn.2020.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573194PMC
September 2020

Brain Arteriovenous Malformation Recurrence After Apparent Microsurgical Cure: Increased Risk in Children Who Present With Arteriovenous Malformation Rupture.

Stroke 2020 10 11;51(10):2990-2996. Epub 2020 Sep 11.

Division of Neurointerventional Radiology, Department of Radiology and Biomedical Imaging (A.C., G.D., M.T.C., E.R.S., D.L.C., M.R.A., C.F.D., V.V.H., R.T.H., S.W.H.), University of California, San Francisco.

Background And Purpose: Do children have an increased risk for brain arteriovenous malformation (AVM) recurrence compared with adults and does this risk vary depending on initial presentation with AVM rupture?

Methods: We retrospectively studied 115 patients initially presenting with brain AVM under age 25 years who underwent complete surgical resection of the AVM as documented by digital subtraction angiography (DSA) and had delayed follow-up DSA to evaluate for AVM recurrence after apparent initial cure.

Results: The mean time from baseline DSA to follow-up DSA was 2.3 years, ranging from 0 to 15 years. Twelve patients (10.4% of the 115 patient cohort and 16.7% of 72 patients with hemorrhage at initial presentation) demonstrated AVM recurrence on follow-up DSA. All patients with recurrence initially presented with intracranial hemorrhage, and intracranial hemorrhage was a significant predictor of recurrence (log rank =0.037). Among patients with initial hemorrhage, the 5-year recurrence rate was 17.8% (95% CI, 8.3%-35.7%). All recurrences occurred in patients who were children at the time of their initial presentation; the oldest was 15 years of age at the time of initial AVM surgery. The 5-year recurrence rate for children (0-18 years of age) with an initial presentation of hemorrhage was 21.4% (95% CI, 10.1%-41.9%). Using Cox regression, we found the risk of AVM recurrence decreased by 14% per each year increase in age at the time of initial surgical resection (hazard ratio=0.86 [95% CI, 0.75-0.99]; =0.031).

Conclusions: There is a high rate of recurrence of apparently cured brain AVMs in children who initially present with AVM rupture. Imaging follow-up is warranted to prevent re-rupture.
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http://dx.doi.org/10.1161/STROKEAHA.120.030135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731776PMC
October 2020

Monitoring Arteriovenous Malformation Response to Genotype-Targeted Therapy.

Pediatrics 2020 09;146(3)

Pediatrics, University of California San Francisco, San Francisco, California.

Arteriovenous malformations (AVMs) have recently been reported to have a high incidence of somatic KRAS mutations suggesting potential for treatment with mitogen-activated protein kinase inhibitors. In this case report, we describe genotype-targeted treatment of a KRAS mutant metameric AVM in a patient with Cobb syndrome using the mitogen-activated protein kinase inhibitor trametinib. Therapeutic response was monitored with phase-contrast magnetic resonance angiography to quantify AVM arterial inflow as an imaging biomarker. Treatment with trametinib resulted in a substantial decrease in blood flow to the AVM, with a >75% reduction in arterial inflow after 6 months of trametinib therapy.
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http://dx.doi.org/10.1542/peds.2019-3206DOI Listing
September 2020

Validation of the focal cerebral arteriopathy severity score (FCASS) in a Swiss cohort: Correlation with infarct volume and outcome.

Eur J Paediatr Neurol 2020 Sep 4;28:58-63. Epub 2020 Aug 4.

Division of Neuropaediatrics, University Hospital Inselspital, and University of Bern, Switzerland.

Background: Focal cerebral arteriopathy (FCA), a major cause of childhood arterial ischemic stroke (AIS), can progress and lead to increased infarct size and/or recurrent stroke. Evaluating treatment options depends on the ability to quantify reliably the degree of stenosis in FCA.

Aims: We validated the recently introduced FCA severity score (FCASS) in an independent cohort from the Swiss Neuro-Paediatric Stroke Registry (SNPSR).

Materials And Methods: We included children with FCA who had MR or CT angiography and a Pediatric Stroke Outcome Measure (PSOM) at 6-months and 2-years post-stroke. A paediatric neuroradiologist applied the FCASS and the modified pediatric Alberta Stroke Program Early Computed Tomography Score (ASPECTS), a measure of infarct volume, to all available imaging. Two senior paediatric stroke neurologists and a neuroradiology fellow independently assigned FCASS scores to test interrater reliability. Pairwise correlations between FCASS, pedASPECTS, and PSOM were examined.

Results: Thirty-two children [median (IQR) age = 5.9 (1.8, 9.6), 19 males] were included. The median maximum FCASS score at any time was 9 (IQR 6, 12; range 3, 16). Larger infarct volume scores correlated with both higher maximum FCASS scores and worse post-stroke outcomes, although we found no direct correlation between FCASS and outcomes. Stroke neurologists tended to assign lower FCASS scores than the neuroradiologist, but interrater reliability was predominantly good.

Conclusions: In this independent validation cohort, higher maximum FCASS correlated with greater infarct volume scores that also correlated with worse neurological outcomes. Scoring by non-imaging specialists seems to be valuable, although differences are present.
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http://dx.doi.org/10.1016/j.ejpn.2020.07.015DOI Listing
September 2020

Single-center series of boys with recurrent strokes and rotational vertebral arteriopathy.

Neurology 2020 09 20;95(13):e1830-e1834. Epub 2020 Jul 20.

From the Departments of Neurology (C.K.F., H.J.F.), Pediatrics (C.K.F., H.J.F., K.I.A., N.G.), Radiology and Biomedical Imaging (S.W.H., V.V.H.), and Neurological Surgery (K.I.A., M.T.L., N.G.), University of California San Francisco; and Department of Neurological Surgery (M.T.L.), Barrow Neurological Institute, Phoenix, AZ.

Objective: To describe a pediatric stroke syndrome with chronic focal vertebral arteriopathy adjacent to cervical abnormalities.

Methods: At a single pediatric stroke center, we identified consecutive children with stroke and vertebral arteriopathy of the V3 segment with adjacent cervical bony or soft tissue abnormalities. We abstracted clinical presentation, treatment, and follow-up data from medical charts.

Results: From 2005 to 2019, 10 children (all boys, ages 6-16 years) presented with posterior circulation strokes and vertebral arteriopathy with adjacent cervical pathology. Two children had bony abnormalities: one had a congenital arcuate foramen and one had os odontoideum with cervical instability. In children without bony pathology, vertebral artery narrowing during contralateral head rotation was visualized by digital subtraction angiography. Eight boys had recurrent ischemic events despite anti-thrombotic treatment (including 5 with multiple recurrences) and were treated surgically to prevent additional stroke. Procedures included vertebral artery decompression (n = 6), endovascular stent and spinal fusion (n = 1), and vertebral artery endovascular occlusion (n = 1). In boys treated with decompression, cervical soft tissue abnormalities (ruptured atlantoaxial bursa, ruptured joint capsule, or connective tissue scarring) were directly visualized during open surgery. No other etiology for stroke or dissection was found in any of the cases. Two boys without recurrent stroke were treated with activity restriction and antithrombotics. At a median follow-up of 51 months (range 17-84), there have been no additional recurrences.

Conclusions: Children with V3 segmental vertebral arteriopathy frequently have stroke recurrence despite antithrombotics. Cervical bone imaging and angiography with neck rotation can identify underlying pathology.
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http://dx.doi.org/10.1212/WNL.0000000000010416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682823PMC
September 2020

Spectrum of cerebral arteriopathies in children with arterial ischemic stroke.

Neurology 2020 06 26;94(23):e2479-e2490. Epub 2020 May 26.

From the Section of Pediatric Neurology (M.F.R.), Department of Pediatrics and Child Health, University of Manitoba, Children's Hospital Research Institute of Manitoba, Winnipeg, Canada; Department of Neurology and Pediatrics (K.A.S., H.J.F.), University of California, San Francisco; University of Toronto (A.-M.S.); Division of Neurology (G.A.d.V., N.D., A.L.), The Hospital for Sick Children, University of Toronto, Ontario; Department of Pediatrics and Clinical Neurosciences (A.K.), Cumming School of Medicine, University of Calgary, Alberta, Canada; Department of Neurology (C.A.-L.), University of Washington, Seattle; Department of Neuropediatrics (B.W.), Charité University Medicine Berlin, Germany; Department of Neurology (J.L.C.), George Washington University, Washington, DC; Department of Neurology (M.T.M.), Royal Children's Hospital Melbourne, Murdoch Children's Research Institute and University of Melbourne, Australia; Boston Children's Hospital (M.R.), Harvard Medical School, Boston, MA; and Division of Child Neurology (T.J.B.), Department of Pediatrics and the Hemophilia and Thrombosis Center, University of Colorado, Denver.

Objective: To determine that children with arterial ischemic stroke (AIS) due to an identifiable arteriopathy are distinct from those without arteriopathy and that each arteriopathy subtype has unique and recognizable clinical features.

Methods: We report a large, observational, multicenter cohort of children with AIS, age 1 month to 18 years, enrolled in the International Pediatric Stroke Study from 2003 to 2014. Clinical and demographic differences were compared by use of the Fisher exact test, with linear step-up permutation min- adjustment for multiple comparisons. Exploratory analyses were conducted to evaluate differences between cases of AIS with and without arteriopathy and between arteriopathy subtypes.

Results: Of 2,127 children with AIS, 725 (34%) had arteriopathy (median age 7.45 years). Arteriopathy subtypes included dissection (27%), moyamoya (24.5%), focal cerebral arteriopathy-inflammatory subtype (FCA-i; 15%), diffuse cerebral vasculitis (15%), and nonspecific arteriopathy (18.5%). Children with arteriopathic AIS were more likely to present between 6 and 9 years of age (odds ratio [OR] 1.93, = 0.029) with headache (OR 1.55, = 0.023), multiple infarctions (OR 2.05, < 0.001), sickle cell anemia (OR 2.9, = 0.007), and head/neck trauma (OR 1.93, = 0.018). Antithrombotic use and stroke recurrence were higher in children with arteriopathy. Among arteriopathy subtypes, dissection was associated with male sex, older age, headache, and anticoagulant use; FCA-i was associated with hemiparesis and single infarcts; moyamoya was associated with seizures and recurrent strokes; and vasculitis was associated with bilateral infarctions.

Conclusion: Specific clinical profiles are associated with cerebral arteriopathies in children with AIS. These observations may be helpful indicators in guiding early diagnosis and defining subgroups who may benefit most from future therapeutic trials.
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http://dx.doi.org/10.1212/WNL.0000000000009557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455362PMC
June 2020

Neuroimaging of Pediatric Intracerebral Hemorrhage.

J Clin Med 2020 May 18;9(5). Epub 2020 May 18.

Pediatric Radiology Department, Necker Enfants Malades & GHU Paris, Sainte-Anne Hospital, Institut de Psychiatrie et Neurosciences de Paris (IPNP), UMR S1266, INSERM, Université de Paris, 75015 Paris, France.

Hemorrhagic strokes account for half of all strokes seen in children, and the etiologies of these hemorrhagic strokes differ greatly from those seen in adult patients. This review gives an overview about incidence and etiologies as well as presentation of children with intracerebral hemorrhage and with differential diagnoses in the emergency department. Most importantly it describes how neuroimaging of children with intracerebral hemorrhage should be tailored to specific situations and clinical contexts and recommends specific imaging protocols for acute and repeat imaging. In this context it is important to keep in mind the high prevalence of underlying vascular lesions and adapt the imaging protocol accordingly, meaning that vascular imaging plays a key role regardless of modality. Magnetic resonance imaging (MRI), including advanced sequences, should be favored whenever possible at the acute phase.
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http://dx.doi.org/10.3390/jcm9051518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290500PMC
May 2020

Bringing high-grade arteriovenous malformations under control: clinical outcomes following multimodality treatment in children.

J Neurosurg Pediatr 2020 Apr 10:1-10. Epub 2020 Apr 10.

Departments of1Neurological Surgery.

Objective: Brain arteriovenous malformations (AVMs) consist of dysplastic blood vessels with direct arteriovenous shunts that can hemorrhage spontaneously. In children, a higher lifetime hemorrhage risk must be balanced with treatment-related morbidity. The authors describe a collaborative, multimodal strategy resulting in effective and safe treatment of pediatric AVMs.

Methods: A retrospective analysis of a prospectively maintained database was performed in children with treated and nontreated pediatric AVMs at the University of California, San Francisco, from 1998 to 2017. Inclusion criteria were age ≤ 18 years at time of diagnosis and an AVM confirmed by a catheter angiogram.

Results: The authors evaluated 189 pediatric patients with AVMs over the study period, including 119 ruptured (63%) and 70 unruptured (37%) AVMs. The mean age at diagnosis was 11.6 ± 4.3 years. With respect to Spetzler-Martin (SM) grade, there were 38 (20.1%) grade I, 40 (21.2%) grade II, 62 (32.8%) grade III, 40 (21.2%) grade IV, and 9 (4.8%) grade V lesions. Six patients were managed conservatively, and 183 patients underwent treatment, including 120 resections, 82 stereotactic radiosurgery (SRS), and 37 endovascular embolizations. Forty-four of 49 (89.8%) high-grade AVMs (SM grade IV or V) were treated. Multiple treatment modalities were used in 29.5% of low-grade and 27.3% of high-grade AVMs. Complete angiographic obliteration was obtained in 73.4% of low-grade lesions (SM grade I-III) and in 45.2% of high-grade lesions. A periprocedural stroke occurred in a single patient (0.5%), and there was 1 treatment-related death. The mean clinical follow-up for the cohort was 4.1 ± 4.6 years, and 96.6% and 84.3% of patients neurologically improved or remained unchanged in the ruptured and unruptured AVM groups following treatment, respectively. There were 16 bleeding events following initiation of AVM treatment (annual rate: 0.02 events per person-year).

Conclusions: Coordinated multidisciplinary evaluation and individualized planning can result in safe and effective treatment of children with AVMs. In particular, it is possible to treat the majority of high-grade AVMs with an acceptable safety profile. Judicious use of multimodality therapy should be limited to appropriately selected patients after thorough team-based discussions to avoid additive morbidity. Future multicenter studies are required to better design predictive models to aid with patient selection for multimodal pediatric care, especially with high-grade AVMs.
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http://dx.doi.org/10.3171/2020.1.PEDS19487DOI Listing
April 2020

High-Flow Vascular Malformations in Children.

Semin Neurol 2020 06 6;40(3):303-314. Epub 2020 Apr 6.

Department of Neurological Surgery, University of California San Francisco, San Francisco, California.

Children can have a variety of intracranial vascular anomalies ranging from small and incidental with no clinical consequences to complex lesions that can cause substantial neurologic deficits, heart failure, or profoundly affect development. In contrast to high-flow lesions with direct arterial-to-venous shunts, low-flow lesions such as cavernous malformations are associated with a lower likelihood of substantial hemorrhage, and a more benign course. Management of vascular anomalies in children has to incorporate an understanding of how treatment strategies may affect the normal development of the central nervous system. In this review, we discuss the etiologies, epidemiology, natural history, and genetic risk factors of three high-flow vascular malformations seen in children: brain arteriovenous malformations, intracranial dural arteriovenous fistulas, and vein of Galen malformations.
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http://dx.doi.org/10.1055/s-0040-1708869DOI Listing
June 2020

Stroke impact on mortality and psychologic morbidity within the Childhood Cancer Survivor Study.

Cancer 2020 03 6;126(5):1051-1059. Epub 2019 Dec 6.

Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Poor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).

Methods: The CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.

Results: Among 14,358 participants (median age, 39.7 years), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).

Conclusions: Stroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer.
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http://dx.doi.org/10.1002/cncr.32612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528606PMC
March 2020

A pragmatic, adaptive clinical trial design for a rare disease: The FOcal Cerebral Arteriopathy Steroid (FOCAS) trial.

Contemp Clin Trials 2019 11 13;86:105852. Epub 2019 Oct 13.

Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, United States. Electronic address:

Background: Pediatric stroke investigators identified as their top research priority a clinical trial of corticosteroids for focal cerebral arteriopathy (FCA). However, FCA is both rare and an acute condition making it infeasible to enroll the large sample sizes needed for standard, confirmatory clinical trials. We present a pragmatic approach to clinical trial design that may inform the approach to other rare disorders.

Methods: We surveyed pediatric stroke experts to determine the level of evidence that would impact their clinical management of FCA. Incorporating survey results, a randomized, group sequential Bayesian adaptive design was proposed based on a quantitative radiologic outcome measure (change from baseline in change in the FCA Severity Score). Using accumulating information, the design determines whether intervention is better than control with high probability.

Results: Among 21 (100%) respondents, the probability of corticosteroid efficacy that would lead the experts to treat was 30% (median). The probability of efficacy that would make them unwilling to randomize (because they would feel all children should receive corticosteroids) was 70%. Simulation studies with the proposed design showed that a total of 42 subjects controls the type I error rate at the desired level 0.20 and yields a smaller average sample size and trial duration compared to a conventional design.

Conclusions: Designs in rare diseases require special considerations; this is especially true for this childhood disease, which is both uncommon and acute. This design has incorporated expert consensus to establish the criteria for success, formal monitoring rules for safety, and early stopping rules.
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http://dx.doi.org/10.1016/j.cct.2019.105852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857809PMC
November 2019

Building a Career as a Pediatric Stroke Neurologist.

Stroke 2019 10 12;50(10):e287-e289. Epub 2019 Sep 12.

Department of Pediatric Neurology, University Children's Hospital, University of Bern, Switzerland (M.S.).

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http://dx.doi.org/10.1161/STROKEAHA.119.026187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756932PMC
October 2019

Ischemic stroke in children and young adults with sickle cell disease in the post-STOP era.

Am J Hematol 2019 12 1;94(12):1335-1343. Epub 2019 Nov 1.

Department of Neurology, Medical University of South Carolina, Charleston, South Carolina.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trials established routine transcranial Doppler ultrasound (TCD) screening, with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. Implementation failures and limitations to the STOP protocol may contribute to continued ischemic stroke occurrence. In the "Post-STOP" study, we sought to assess the impact of the STOP protocol on the incidence of ischemic stroke in a multicenter cohort of former STOP and/or STOP 2 trial participants. A central team abstracted data for 2851 (74%) of the 3835 children who took part in STOP and/or STOP 2. Data included TCD and neuroimaging results, treatment, laboratory data, and detailed clinical information pertaining to the stroke. Two stroke neurologists independently confirmed each stroke using pre-specified imaging and clinical criteria and came to consensus. Among the 2808 patients who were stroke-free at the start of Post-STOP with available follow-up, the incidence of first ischemic stroke was 0.24 per 100 patient-years (95% CI, 0.18, 0.31), with a mean (SD) duration of follow-up of 9.1 (3.4) [median 10.3, range (0-15.4)] years. Most (63%) strokes occurred in patients in whom the STOP protocol had not been properly implemented, either failure to screen appropriately with TCD (38%) or failure to transfuse adequately patients with abnormal TCD (25%). This study shows that substantial opportunities for ischemic stroke prevention remain by more complete implementation of the STOP Protocol.
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http://dx.doi.org/10.1002/ajh.25635DOI Listing
December 2019

Management of Stroke in Neonates and Children: A Scientific Statement From the American Heart Association/American Stroke Association.

Stroke 2019 03;50(3):e51-e96

Purpose- Much has transpired since the last scientific statement on pediatric stroke was published 10 years ago. Although stroke has long been recognized as an adult health problem causing substantial morbidity and mortality, it is also an important cause of acquired brain injury in young patients, occurring most commonly in the neonate and throughout childhood. This scientific statement represents a synthesis of data and a consensus of the leading experts in childhood cardiovascular disease and stroke. Methods- Members of the writing group were appointed by the American Heart Association Stroke Council's Scientific Statement Oversight Committee and the American Heart Association's Manuscript Oversight Committee and were chosen to reflect the expertise of the subject matter. The writers used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. This scientific statement is based on expert consensus considerations for clinical practice. Results- Annualized pediatric stroke incidence rates, including both neonatal and later childhood stroke and both ischemic and hemorrhagic stroke, range from 3 to 25 per 100 000 children in developed countries. Newborns have the highest risk ratio: 1 in 4000 live births. Stroke is a clinical syndrome. Delays in diagnosis are common in both perinatal and childhood stroke but for different reasons. To develop new strategies for prevention and treatment, disease processes and risk factors that lead to pediatric stroke are discussed here to aid the clinician in rapid diagnosis and treatment. The many important differences that affect the pathophysiology and treatment of childhood stroke are discussed in each section. Conclusions- Here we provide updates on perinatal and childhood stroke with a focus on the subtypes, including arterial ischemic, venous thrombotic, and hemorrhagic stroke, and updates in regard to areas of childhood stroke that have not received close attention such as sickle cell disease. Each section is highlighted with considerations for clinical practice, attendant controversies, and knowledge gaps. This statement provides the practicing provider with much-needed updated information in this field.
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http://dx.doi.org/10.1161/STR.0000000000000183DOI Listing
March 2019

Genetic and Environmental Associations With Pediatric Cerebral Arteriopathy.

Stroke 2019 02;50(2):257-265

Clinical Neurosciences, UCL Great Ormond Street Institute of Child Health, London (V.G.).

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http://dx.doi.org/10.1161/STROKEAHA.118.020479DOI Listing
February 2019

Focal Cerebral Arteriopathy of Childhood: Novel Severity Score and Natural History.

Stroke 2018 11;49(11):2590-2596

Division of Neuroradiology, Department of Radiology, Stanford University, CA (B.J., M.W.).

Background and Purpose- Focal cerebral arteriopathy (FCA)-a common cause of arterial ischemic stroke in previously healthy children-often progresses over days to weeks, increasing the risk of recurrent stroke. We developed a novel severity scoring system designed to quantify FCA progression and correlate with clinical outcomes. Methods- The VIPS study (Vascular Effects of Infection in Pediatric Stroke) prospectively enrolled 355 children with arterial ischemic stroke (2010-2014), including 41 with centrally confirmed FCA. Two neuroradiologists independently reviewed FCA cerebrovascular imaging, assigning a graded severity score of zero (no involvement) to 4 (occlusion) to individual arterial segments. The FCA severity score (FCASS) was the unweighted sum. In an iterative process, we modeled scores derived from different combinations of arterial segments to identify the model that optimized correlation with clinical outcome, simplicity, and reliability. Results- The optimal FCASS summed scores from 5 arterial segments: supraclinoid internal carotid artery, A1, A2, M1, and M2. The median (interquartile range) baseline FCASS was 4 (2-6). Of 33 children with follow-up imaging, the maximum FCASS (at any time point) was 7 (5-9). Twenty-four (73%) had FCA progression on follow-up with their maximum FCASS at a median of 8 (5-35.5) days poststroke; their median FCASS increase was 4 (2.5-6). FCASS did not correlate with recurrent arterial ischemic stroke. Maximum (but not baseline) FCASS correlated with 1-year pediatric stroke outcome measures ( P=0.037). Conclusions- Our novel scoring system for FCA severity correlates with neurological outcomes in the VIPS cohort and provides a tool for FCA treatment trials under development.
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http://dx.doi.org/10.1161/STROKEAHA.118.021556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334774PMC
November 2018

Socioeconomic determinants of outcome after childhood arterial ischemic stroke.

Neurology 2018 08 6;91(6):e509-e516. Epub 2018 Jul 6.

From the Department of Pediatrics (L.C.J.), Division of Pediatric Neurology, Vanderbilt University Medical Center, Nashville, TN; Departments of Neurology (N.K.H., C.K.F., H.J.F.), Biostatistics and Epidemiology (N.K.H.), and Pediatrics (C.K.F., H.J.F.), University of California San Francisco; Department of Neurology (R.N.I.), The Children's Hospital of Philadelphia, PA; Department of Neurology (P.P.), Children's National Medical Center, Washington, DC; Department of Neurology (G.A.d.V.), Hospital for Sick Children, Toronto, Ontario, Canada; and Department of Neurology (W.L.), Nationwide Children's Hospital, Columbus, OH.

Objective: To determine whether lower socioeconomic status (SES) is associated with worse 1-year neurologic outcomes and reduced access to rehabilitation services in children with arterial ischemic stroke (AIS).

Methods: From 2010 to 2014, the Vascular effects of Infection in Pediatric Stroke (VIPS) observational study prospectively enrolled and confirmed 355 children (age 29 days-18 years) with AIS at 37 international centers. SES markers measured via parental interview included annual household income (US dollars) at the time of enrollment, maternal education level, and rural/suburban/urban residence. Receipt of rehabilitation services was measured by parental report. Pediatric Stroke Outcome Measure scores were categorized as 0 to 1, 1.5 to 3, 3.5 to 6, and 6.5 to 10. Univariate and multivariable ordinal logistic regression models examined potential predictors of outcome.

Results: At 12 ± 3 months after stroke, 320 children had documented outcome measurements, including 15 who had died. In univariate analysis, very low income (
Conclusions: In a large, multinational, prospective cohort of children with AIS, low income was associated with worse neurologic outcomes compared to higher income levels. This difference was not explained by stroke type, neurologic comorbidities, or reported use of rehabilitation services. The root causes of this disparity are not clear and warrant further investigation.
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http://dx.doi.org/10.1212/WNL.0000000000005946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105045PMC
August 2018

Population-based study of ischemic stroke risk after trauma in children and young adults.

Neurology 2017 Dec 8;89(23):2310-2316. Epub 2017 Nov 8.

From the Departments of Neurology (C.K.F., A.L.N., H.J.F.), Pediatrics (C.K.F., A.L.N., H.J.F.), Epidemiology and Biostatistics (N.K.H.), and Surgery (R.A.D.), University of California, San Francisco; the Division of Research (D.R.V., S.S.), Kaiser Permanente Northern California, Oakland; and the Department of Emergency Medicine (D.R.V.), Kaiser Permanente Sacramento Medical Center, Sacramento, CA.

Objective: To quantify the incidence, timing, and risk of ischemic stroke after trauma in a population-based young cohort.

Methods: We electronically identified trauma patients (<50 years old) from a population enrolled in a Northern Californian integrated health care delivery system (1997-2011). Within this cohort, we identified cases of arterial ischemic stroke within 4 weeks of trauma and 3 controls per case. A physician panel reviewed medical records, confirmed cases, and adjudicated whether the stroke was related to trauma. We calculated the 4-week stroke incidence and estimated stroke odds ratios (OR) by injury location using logistic regression.

Results: From 1,308,009 trauma encounters, we confirmed 52 trauma-related ischemic strokes. The 4-week stroke incidence was 4.0 per 100,000 encounters (95% confidence interval [CI] 3.0-5.2). Trauma was multisystem in 26 (50%). In 19 (37%), the stroke occurred on the day of trauma, and all occurred within 15 days. In 7/28 cases with cerebrovascular angiography at the time of trauma, no abnormalities were detected. In unadjusted analyses, head, neck, chest, back, and abdominal injuries increased stroke risk. Only head (OR 4.1, CI 1.1-14.9) and neck (OR 5.6, CI 1.03-30.9) injuries remained associated with stroke after adjusting for demographics and trauma severity markers (multisystem trauma, motor vehicle collision, arrival by ambulance, intubation).

Conclusions: Stroke risk is elevated for 2 weeks after trauma. Onset is frequently delayed, providing an opportunity for stroke prevention during this period. However, in one-quarter of stroke cases with cerebrovascular angiography at the time of trauma, no vascular abnormality was detected.
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http://dx.doi.org/10.1212/WNL.0000000000004708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5719927PMC
December 2017

Parvovirus B19 Infection in Children With Arterial Ischemic Stroke.

Stroke 2017 10 1;48(10):2875-2877. Epub 2017 Sep 1.

From the Department of Neurology (H.J.F.), Department of Pediatrics (H.J.F.), and Department of Biostatistics and Epidemiology (N.K.H.), University of California, San Francisco; Department of Epidemiology (J.M.L., R.T., W.I.L., M.S.V.E.) and Department of Neurology (M.S.V.E.), Columbia University College of Physicians and Surgeons, New York, NY; Department of Radiology, Stanford University, Palo Alto, CA (M.W., Y.L.); Department of Pediatrics (Infectious Disease), Kaiser Permanente, Oakland, CA (C.G.); and Department of Neurology, Hospital for Sick Children, Toronto, Canada (G.A.D.).

Background And Purpose: Case-control studies suggest that acute infection transiently increases the risk of childhood arterial ischemic stroke. We hypothesized that an unbiased pathogen discovery approach utilizing MassTag-polymerase chain reaction would identify pathogens in the blood of childhood arterial ischemic stroke cases.

Methods: The multicenter international VIPS study (Vascular Effects of Infection in Pediatric Stroke) enrolled arterial ischemic stroke cases, and stroke-free controls, aged 29 days through 18 years. Parental interview included questions on recent infections. In this pilot study, we used MassTag-polymerase chain reaction to test the plasma of the first 161 cases and 34 controls enrolled for a panel of 28 common bacterial and viral pathogens.

Results: Pathogen DNA was detected in no controls and 14 cases (8.7%): parvovirus B19 (n=10), herpesvirus 6 (n=2), adenovirus (n=1), and rhinovirus 6C (n=1). Parvovirus B19 infection was confirmed by serologies in all 10; infection was subclinical in 8. Four cases with parvovirus B19 had underlying congenital heart disease, whereas another 5 had a distinct arteriopathy involving a long-segment stenosis of the distal internal carotid and proximal middle cerebral arteries.

Conclusions: Using MassTag-polymerase chain reaction, we detected parvovirus B19-a virus known to infect erythrocytes and endothelial cells-in some cases of childhood arterial ischemic stroke. This approach can generate new, testable hypotheses about childhood stroke pathogenesis.
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http://dx.doi.org/10.1161/STROKEAHA.117.018272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614850PMC
October 2017

Pediatric intracranial dural arteriovenous fistulas: age-related differences in clinical features, angioarchitecture, and treatment outcomes.

J Neurosurg Pediatr 2016 Nov 19;18(5):602-610. Epub 2016 Aug 19.

Departments of 1 Radiology and Biomedical Imaging.

OBJECTIVE Intracranial dural arteriovenous fistulas (DAVFs) are rare in children. This study sought to better characterize DAVF presentation, angioarchitecture, and treatment outcomes. METHODS Children with intracranial DAVFs between 1986 and 2013 were retrospectively identified from the neurointerventional database at the authors' institution. Demographics, clinical presentation, lesion angioarchitecture, treatment approaches, angiographic outcomes, and clinical outcomes were assessed. RESULTS DAVFs constituted 5.7% (22/423) of pediatric intracranial arteriovenous shunting lesions. Twelve boys and 10 girls presented between 1 day and 18 years of age; boys presented at a median of 1.3 years and girls presented at a median of 4.9 years. Four of 8 patients ≤ 1 year of age presented with congestive heart failure compared with 0/14 patients > 1 year of age (p = 0.01). Five of 8 patients ≤ 1 year old presented with respiratory distress compared with 0/14 patients > 1 year old (p = 0.0021). Ten of 14 patients > 1 year old presented with focal neurological deficits compared with 0/8 patients ≤ 1 year old (p = 0.0017). At initial angiography, 16 patients harbored a single intracranial DAVF and 6 patients had 2-6 DAVFs. Eight patients (38%) experienced DAVF obliteration by the end of treatment. Good clinical outcome (modified Rankin Scale score 0-2) was documented in 77% of patients > 1 year old at presentation compared with 57% of patients ≤ 1 year old at presentation. Six patients (27%) died. CONCLUSIONS Young children with DAVFs presented predominantly with cardiopulmonary symptoms, while older children presented with focal neurological deficits. Compared with other pediatric vascular shunts, DAVFs had lower rates of angiographic obliteration and poorer clinical outcomes.
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http://dx.doi.org/10.3171/2016.5.PEDS15740DOI Listing
November 2016

Transcranial doppler re-screening of subjects who participated in STOP and STOP II.

Am J Hematol 2016 12 25;91(12):1191-1194. Epub 2016 Oct 25.

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

In children with Sickle Cell Disease, the combination of risk stratification with Transcranial Doppler Ultrasound (TCD) and selective chronic red cell transfusion (CRCT-the STOP Protocol) is one of the most effective stroke prevention strategies in medicine. How fully it is being implemented is unclear. Nineteen of 26 sites that conducted the two pivotal clinical trials (STOP and STOP II) participated in Post STOP, a comprehensive medical records review assessing protocol implementation in the 10-15 years since the trials ended. Professional abstractors identified medical records in the Post STOP era in 2851 (74%) of the 3,840 children who took part in STOP and/or STOP II, and documented TCD rescreening, maintenance of CRCT in those at risk, and stroke. Among 1,896 children eligible for TCD rescreening (target group), evidence of any rescreening was found in 1,090 (57%). There was wide site variation in TCD rescreening ranging from 18% to 91% of eligible children. Both younger age and having a conditional TCD during STOP/II were associated with a higher likelihood of having a TCD in Post STOP. Sixty eight new abnormal, high risk cases were identified. Despite clear evidence of benefit the STOP protocol is not fully implemented even at experienced sites. Site variation suggests that system improvements might remove barriers to implementation and result in even greater reduction of ischemic stroke in children with SCD. Am. J. Hematol. 91:1191-1194, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajh.24551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155448PMC
December 2016

Inter-Rater Reliability of the CASCADE Criteria: Challenges in Classifying Arteriopathies.

Stroke 2016 10 15;47(10):2443-9. Epub 2016 Sep 15.

From the Section of Child Neurology (T.J.B., J.A.-W., R.B.), Section of Hematology/Oncology/BMT (M.J.M.-J.), Hemophilia and Thrombosis Center, Department of Pediatrics (T.J.B., M.J.M.-J., J.A.-W., A.H.), Department of Pediatrics (T.J.B, M.J.M-J, J.A-W., R.B.), Department of Biostatistics and Informatics, School of Public Health (D.W.), and Department of Neurology (S.P.), University of Colorado, Aurora; Division of Child Neurology (L.A.B.), Department of Pediatrics (L.A.B.), and Department of Neurology (L.A.B.), Yale School of Medicine, New Haven, CT; University of Washington (C.A.L.); Department of Pediatrics (W.L., E.S.R.) and Department of Neurology (W.L., E.S.R.), The Ohio State University and Nationwide Children's Hospital, Columbus; Hospital for Sick Children, University of Toronto, Ontario, Canada (G.d.V.); Division of Hematology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD (N.A.G.); All Children's Research Institute, Johns Hopkins All Children's Hospital, St. Petersburg, FL (N.A.G.); Division of Pediatric Neurology, Department of Pediatrics (M.M.D.) and Department of Neurology and Neurotherapeutics (M.M.D.), UT Southwestern Medical Center, Dallas, TX; Division of Neurology, University of California, San Francisco (H.J.F.); Rheumatology Clinic, Department of Pediatrics, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Canada (S.M.B.); Division of Pediatric Neurology, Department of Pediatrics, Vanderbilt University Medical Center (L.C.J.); Calgary Pediatric Stroke Program, Division of Neurology, Alberta Children's Hospital, University of Calgary, Canada (A.K.); and Department Neurology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine (R.N.I.).

Background And Purpose: There are limited data about the reliability of subtype classification in childhood arterial ischemic stroke, an issue that prompted the IPSS (International Pediatric Stroke Study) to develop the CASCADE criteria (Childhood AIS Standardized Classification and Diagnostic Evaluation). Our purpose was to determine the CASCADE criteria's reliability in a population of children with stroke.

Methods: Eight raters from the IPSS reviewed neuroimaging and clinical records of 64 cases (16 cases each) randomly selected from a prospectively collected cohort of 113 children with arterial ischemic stroke and classified them using the CASCADE criteria. Clinical data abstracted included history of present illness, risk factors, and acute imaging. Agreement among raters was measured by unweighted κ statistic.

Results: The CASCADE criteria demonstrated a moderate inter-rater reliability, with an overall κ statistic of 0.53 (95% confidence interval [CI]=0.39-0.67). Cardioembolic and bilateral cerebral arteriopathy subtypes had much higher agreement (κ=0.84; 95% CI=0.70-0.99; and κ=0.90; 95% CI=0.71-1.00, respectively) than cases of aortic/cervical arteriopathy (κ=0.36; 95% CI=0.01-0.71), unilateral focal cerebral arteriopathy of childhood (FCA; κ=0.49; 95% CI=0.23-0.76), and small vessel arteriopathy of childhood (κ=-0.012; 95% CI=-0.04 to 0.01).

Conclusions: The CASCADE criteria have moderate reliability when used by trained and experienced raters, which suggests that it can be used for classification in multicenter pediatric stroke studies. However, the moderate reliability of the arteriopathic subtypes suggests that further refinement is needed for defining subtypes. Such revisions may reduce the variability in the literature describing risk factors, recurrence, and outcomes associated with childhood arteriopathy.
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http://dx.doi.org/10.1161/STROKEAHA.116.013544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764077PMC
October 2016

Presence of cerebral microbleeds is associated with worse executive function in pediatric brain tumor survivors.

Neuro Oncol 2016 11 18;18(11):1548-1558. Epub 2016 Aug 18.

School of Medicine University of California San Francisco (UCSF), San Francisco, California (E.R.); Department of Neurology UCSF, San Francisco, California (K.S., E.F., B.D.B., H.J.F., S.M.); D epartment of Radiology Children's Hospital Los Angeles, Los Angeles, California (B.T.); Department of Pediatrics, Washington University, St Louis, Missouri (K.G.); Department of Pediatrics, Benioff Children's Hospital Oakland, Oakland, California (J.T.); Department of Pediatrics, Valley Children's Hospital, Madera, California (D.S.); Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts (D.A.H.-K.); Department of Radiation Oncology UCSF, San Francisco, California (J.C.); Department of Pediatrics UCSF, San Francisco, California (R.E.G., A.B., S.M.); Department of Neurological Surgery UCSF, San Francisco, California (A.B., A.M.M., S.M.); Department of Radiology and Biomedical Imaging UCSF, San Francisco, California (J.M.L.); Department of Biostatistics and Epidemiology UCSF, San Francisco, California (A.M.M.)

Background: A specific form of small-vessel vasculopathy-cerebral microbleeds (CMBs)-has been linked to various types of dementia in adults. We assessed the incidence of CMBs and their association with neurocognitive function in pediatric brain tumor survivors.

Methods: In a multi-institutional cohort of 149 pediatric brain tumor patients who received cranial radiation therapy (CRT) between 1987 and 2014 at age <21 years and 16 patients who did not receive CRT, we determined the presence of CMBs on brain MRIs. Neurocognitive function was assessed using a computerized testing program (CogState). We used survival analysis to determine cumulative incidence of CMBs and Poisson regression to examine risk factors for CMBs. Linear regression models were used to assess effect of CMBs on neurocognitive function.

Results: The cumulative incidence of CMBs was 48.8% (95% CI: 38.3-60.5) at 5 years. Children who had whole brain irradiation developed CMBs at a rate 4 times greater than those treated with focal irradiation (P < .001). In multivariable analysis, children with CMBs performed worse on the Groton Maze Learning test (GML) compared with those without CMBs (Z-score -1.9; 95% CI: -2.7, -1.1; P < .001), indicating worse executive function when CMBs are present. CMBs in the frontal lobe were associated with worse performance on the GML (Z-score -2.4; 95% CI: -2.9, -1.8; P < .001). Presence of CMBs in the temporal lobes affected verbal memory (Z-score -2.0; 95% CI: -3.3, -0.7; P = .005).

Conclusion: CMBs are common and associated with neurocognitive dysfunction in pediatric brain tumor survivors treated with radiation.
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http://dx.doi.org/10.1093/neuonc/now163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063522PMC
November 2016

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke: Correlates of Stroke Cause and Recurrence.

Stroke 2016 09 4;47(9):2221-8. Epub 2016 Aug 4.

From the Departments of Neurology (H.J.F., N.K.H., C.K.F.), Pediatrics (H.J.F., C.K.F.), and Biostatistics and Epidemiology (N.K.H.), University of California San Francisco; Department of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada (G.A.d.); Departments of Pediatrics and Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, TX (M.M.D.); Children's Neuroscience Centre, Royal Children's Hospital, Parkville, Victoria, Australia (M.T.M.); Departments of Pediatrics and Clinical Neurosciences, University of Calgary, Alberta, Canada (A.K.); Department of Pediatrics, University of Alberta, Edmonton, Canada (J.Y.Y.); Department of Pediatrics, University of Colorado, Denver (T.J.B.); Departments of Pathology (E.A.H.) and Neurology (M.S.V.E.), Columbia University College of Physicians and Surgeons, New York, NY; Department of Epidemiology, Mailman School of Public Health, New York, NY (M.S.V.E.); and Department of Radiology, Stanford University, Palo Alto, CA (M.W.).

Background And Purpose: Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS.

Methods: In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS.

Results: Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies.

Conclusions: Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.
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http://dx.doi.org/10.1161/STROKEAHA.116.013719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4995134PMC
September 2016
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