Catherine Amlie-Lefond

Predictors of Cerebral Arteriopathy in Children With Arterial Ischemic Stroke Results of the International Pediatric Stroke Study

Background— Cerebral arteriopathies, including an idiopathic focal cerebral arteriopathy of childhood (FCA), are common in children with arterial ischemic stroke and strongly predictive of recurrence. To better understand these lesions, we measured predictors of arteriopathy within a large international series of children with arterial ischemic stroke. Methods and Results— Between January 2003 and July 2007, 30 centers within the International Pediatric Stroke Study enrolled 667 children (age, 29 days to 19 years) with arterial ischemic stroke and abstracted clinical and radiographic data. Cerebral arteriopathy and its subtypes were defined using published definitions; FCA was defined as cerebral arterial stenosis not attributed to specific diagnoses such as moyamoya, arterial dissection, vasculitis, or postvaricella angiopathy. We used multivariate logistic regression techniques to determine predictors of arteriopathy and FCA among those subjects who received vascular imaging. Of 667 subjects, 525 had known vascular imaging results, and 53% of those (n=277) had an arteriopathy. The most common arteriopathies were FCA (n=69, 25%), moyamoya (n=61, 22%), and arterial dissection (n=56, 20%). Predictors of arteriopathy include early school age (5 to 9 years), recent upper respiratory infections, and sickle cell disease, whereas prior cardiac disease and sepsis reduced the risk of arteriopathy. The only predictor of FCA was recent upper respiratory infection. Conclusions— Arteriopathy is prevalent among children with arterial ischemic stroke, particularly those presenting in early school age, and those with a history of sickle cell disease. Recent upper respiratory infection predicted cerebral arteriopathy and FCA in particular, suggesting a possible role for infection in the pathogenesis of these lesions.

Recent developments in childhood arterial ischaemic stroke

Stroke is increasingly recognised as a cause of childhood disability and lifelong morbidity: population-based estimates of the annual incidence of childhood stroke (ischaemic and haemorrhagic) range from 2.3 to 13.0 per 100,000 children, and incidence rates in neonates are closer to 1 per 5000 livebirths. Stroke in childhood can have many causes. Diagnosis is often delayed owing to low clinical suspicion and the need to exclude the frequent mimics of stroke in childhood. Outcomes are related to presentation, associated illnesses, the underlying cause, size, and location of the infarct, and stroke subtype, but more than a half of the children who have had a stroke will have long-term neurological sequelae. Furthermore, estimates of recurrence rates range from 6-19% in the first few years. Arteriopathy-including arterial dissection and other progressive and non-progressive arteriopathies-might account for up to 80% of childhood stroke in otherwise healthy children. Because children with cerebrovascular abnormalities are at the highest risk of recurrence (66% at 5 years), understanding of the nature and course of these arteriopathies is crucial to the development of secondary stroke prevention strategies.

Thrombolysis in Acute Childhood Stroke: Design and Challenges of the Thrombolysis in Pediatric Stroke Clinical Trial

Background: Although tissue plasminogen activator (tPA) has revolutionized the treatment of acute ischemic stroke in adults, no thrombolysis trials in childhood stroke have been conducted. Experience in adults cannot be applied to children due to fundamental age-related differences in coagulation systems, stroke pathophysiology and neuropharmacology. Obstacles to acute treatment trials in childhood stroke include delays in diagnosis and minimizing risk in a vulnerable population. Study Design: Thrombolysis in Pediatric Stroke (TIPS) is an international multicenter study to assess the safety of intravenous tPA within 0–3 h and intra-arterial tPA within 3–6 h of onset of arterial ischemic stroke in childhood. Through the International Pediatric Stroke Study, 30 international centers will enroll a total of 48 patients: 24 will be treated with intravenous tPA (0.6, 0.75, 0.9, and 1.0 mg/kg) using the classical dose-finding method, and 24 will be treated with intra-arterial tPA (maximum 0.2, 0.3, 0.4, and 0.5 mg/kg) using a Bayesian dose-finding method. Conclusion: The TIPS trial will be the first clinical trial exploring the safety and feasibility of systemic and local thrombolytic therapy in childhood stroke and the obstacles in conducting such a trial.

Thrombolysis in Pediatric Stroke Study

Stroke is an important acute neurological condition in children with an annual incidence ranging from 2.3 to 13 per 100 000 children.1–3 Although most children who experience stroke do not die of the acute disorder, the consequences of the brain injury are amortized during the lengthy life span that follows.4–8 The reduction potential in lifelong morbidity by timely and effective intervention with a thrombolytic agent, such as tissue-type plasminogen activator (tPA), in children with acute arterial ischemic stroke (AIS) constituted the core rationale for the study of tPA treatment of acute AIS in children. The perceived high potential for benefit after treatment justified assumption of risk for intracranial hemorrhage (ICH) after its use.9 Because in adults, the risk of hemorrhage after tPA use was thought to be related to infarct volume; this principle was assumed for children. The known developmental trajectory of the fibrinolytic system includes lower levels of endogenous tPA and higher levels of plasminogen activator inhibitor-1 in young children than are found in adults and warranted a dose-finding study beginning at doses lower than that used in adults with incremental increase through the currently used adult dose of 0.9 mg/kg and careful assessment of tPA pharmacokinetics.10 Currently, information on children treated with tPA consists of case reports, small case series, and hospital database documentation. Best practice for the treatment of children with acute stroke has received little rigorous study. Clinical approach varies widely among centers and reflects a dearth of research on which to base treatment protocols. Although tPA is not approved for use in childhood stroke, ≤2% of children with acute stroke are reported to have been treated with tPA in the United States, despite lack of safety and efficacy data.11–14 In 2010, the National Institute …

Emergence of the Primary Pediatric Stroke Center Impact of the Thrombolysis in Pediatric Stroke Trial

Background and Purpose— In adult stroke, the advent of thrombolytic therapy led to the development of primary stroke centers capable to diagnose and treat patients with acute stroke rapidly. We describe the development of primary pediatric stroke centers through preparation of participating centers in the Thrombolysis in Pediatric Stroke (TIPS) trial. Methods— We collected data from the 17 enrolling TIPS centers regarding the process of becoming an acute pediatric stroke center with capability to diagnose, evaluate, and treat pediatric stroke rapidly, including use of thrombolytic therapy. Results— Before 2004, <25% of TIPS sites had continuous 24-hour availability of acute stroke teams, MRI capability, or stroke order sets, despite significant pediatric stroke expertise. After TIPS preparation, >80% of sites now have these systems in place, and all sites reported increased readiness to treat a child with acute stroke. Use of a 1- to 10-Likert scale on which 10 represented complete readiness, median center readiness increased from 6.2 before site preparation to 8.7 at the time of site activation (P⩽0.001). Conclusions— Before preparing for TIPS, centers interested in pediatric stroke had not developed systematic strategies to diagnose and treat acute pediatric stroke. TIPS trial preparation has resulted in establishment of pediatric acute stroke centers with clinical and system preparedness for evaluation and care of children with acute stroke, including use of a standardized protocol for evaluation and treatment of acute arterial stroke in children that includes use of intravenous tissue-type plasminogen activator. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01591096.

Treatment of childhood arterial ischemic stroke.

Traditional risk factors associated with adult arterial ischemic stroke (AIS; ie, hypertension, hyperlipidemia, diabetes, smoking, and atherosclerosis) are relatively rare in children. Childhood AIS is instead associated with a variety of conditions including cerebral arteriopathies, congenital heart disease, infection, head and neck trauma, sickle cell anemia, and prothrombotic abnormalities. Although the pathophysiology and outcomes of adult AIS differ significantly from those in childhood AIS, therapeutic management remains similar, largely because of the paucity of evidence from devoted pediatric observational studies and clinical trials. The purpose of this article is to review the current guidelines and evidence in the treatment of childhood AIS, within the context of that which exists in adult AIS. Medical management of hypoxia, hyperglycemia, fever, blood pressure, and increased intracranial pressure has been insufficiently investigated in childhood stroke, resulting in a lack of guidance in these areas. Although acute antithrombotic management in childhood AIS has received relatively greater attention in published recommendations, it is based almost exclusively on consensus and expert opinion, and differs considerably among existing pediatric guidelines. Rehabilitation therapy in childhood AIS has great potential for meaningful improvements in long‐term outcomes, especially given the plasticity of the young brain; however, little guidance for rehabilitative measures is provided by published recommendations. Ongoing and future multicenter cohort study efforts, and ultimately devoted pediatric clinical trials, will be essential to establish comprehensive evidence‐based guidelines for the treatment of childhood AIS. Ann Neurol 2008

Endovascular therapy in children with acute ischemic stroke Review and recommendations

This review provides a summary of the currently available data pertaining to the interventional management of acute ischemic stroke in children. The literature is scarce and is lacking much-needed prospective trials. No study in the literature on the well-established systemic or local thrombolysis trials has included children. Mechanical thrombectomy trials using clot retriever devices have also excluded patients younger than 18 years. The current review is limited to case series of interventional acute ischemic stroke therapy in children and the potential future of endovascular ischemic stroke therapy in this patient population. Recommendations in this review represent the opinion of the authors, based on review of the limited literature covering endovascular acute ischemic stroke therapy in children.

Innate immunity for biodefense: A strategy whose time has come

Defense against biothreat agents requires a broad-spectrum approach. Modulation of the innate immune system might fulfill this requirement. Hacketts previous review of innate immune activation as a broad-spectrum biodefense strategy identified several unresolved questions. The current article is a systematic approach to answering those questions with the focused participation of research groups developing this technology. Our team of academic and industry participants reviewed the promising agents and came to the following conclusions. It is feasible to construct a biodefense platform combining synergistic agents that activate the innate immune system against a broad range of pathogens on the basis of conserved microbial components by using a nasal spray for immune activation in the respiratory and gastrointestinal tracts because these are the most likely routes of attack. It might also be possible to include agents that inhibit molecular events leading to septic shock. Innate immune-activating agents designed to activate Toll-like and other receptors will probably provide protection against the biothreat pathogen spectrum for periods ranging from 2 to 14 days for IFNs up to 26 weeks for immunomodulatory oligonucleotides. Initial treatment is proposed on the first index case or biosensor alert. Boost doses would be required. Harmful inflammation is possible, but thus far, only transient fever has been observed. Autoimmune reaction and retroviral activation have not been seen thus far in preclinical and human trials of many of these compounds. Toll-like receptor agonists caused cytokine production in all subjects tested, but genetic polymorphism reduced the response to IFN in African American subjects.

Diagnosis and management of pediatric arterial ischemic stroke.

Pediatric stroke is among the top 10 causes of death in children and an important cause of chronic morbidity, with an incidence of 3.3/100,000 children/year. Risk factors associated with stroke in children include cardiac diseases, hematologic and vascular disorders, and infection. Clinical presentation varies depending on age, underlying cause, and stroke location. Antithrombotics and anticoagulants are used in the treatment of pediatric stroke; however, there are no established guidelines for the use of these agents in children. In this article we review the cause, pathophysiology, clinical presentation, diagnosis, acute management, secondary prevention, and outcome of children with stroke. The approach to patients with sickle cell disease and Moyamoya disease is also discussed. Up to date studies to determine the optimal acute treatment of childhood stroke and secondary prevention and risk factor modification are critically needed.

Herpesvirus Infections and Childhood Arterial Ischemic Stroke Results of the VIPS Study

Background— Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. Methods and Results— We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (⩽3 weeks after stroke/trauma); cases had convalescent samples (7–28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1–14.3) years for cases and 10.7 (6.9–13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2–4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. Conclusions— Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.