Pediatric Stroke: Moving the Field Forward

The 2018 AHA/ASA ‘Management of Stroke in Neonates and Children’ is a comprehensive update of the 2008 scientific statement [1, 2]. It highlights the progress that has been made due to better access to care for pediatric patients who are more commonly referred on an emergent basis to children’s hospitals, the improved capability to acquire CT and MR imaging/angiography, state of the art neonatal and pediatric multidisciplinary neurocritical care units, and the increasing number of pediatric neurologists with expertise in the evaluation and management of stroke. Due to a group of highly motivated child neurologists led by Gabrielle deVeber who established the International Pediatric Stroke Study (IPSS) group in 2003 [3, 4], there is an increasing number of clinician investigators focused on pediatric stroke that has resulted in numerous publications as well as in obtaining National Institute of Neurological Disorders and Stroke (NINDS) and other research funding. These efforts have provided a body of evidence that helped craft the ‘considerations for clinical practice’. As the recommendations demonstrate, there remains great reliance on adult stroke data which physicians must selectively extrapolate to make informed decisions. The report was not developed as a ‘guideline’ in which evidence was classified using specified criteria with a formalized approach to linking evidence to recommendations (e.g. Delphi or GRADE) to achieve consensus as is currently done by the AHA/ASA and the American Academy of Neurology but rather as a ‘scientific statement’ [5,6]. This commentary is divided into two sections. The first places the current statement into context by reviewing highlights of the prior 2008 AHA pediatric stroke statement, three subsequent guidelines from other societies and the current report. All provided data and recommendations on pediatric arterial ischemic stroke (AIS), cerebral sinovenous thrombosis (CSVT) and intracerebral hemorrhage (ICH). The second section builds on the AHA statement by presenting observations and suggestions on how to move the field forward. Pediatric stroke is a ‘rare disease’ with all the attendant problems of gaining traction for personnel and in obtaining governmental, institutional and corporate support.

Overview of previous and current guidelines

• AHA Stroke Council statement (2008). This report (524 references:1970-2008; 91 recommendations) was published as a ‘scientific statement’, but in contrast to the 2018 version did include a scheme for classifying and linking the evidence to the strength of the recommendations [2]. At the time of its publication, most guidelines did not have formalized processes for developing consensus. In any event, a broad list of recommendations was made.
• American College of Chest Physicians (2012). The writing group for this guideline (767 references:1965-2011; 60 recommendations) classified the evidence as high, moderate, low or very low and linked the recommendations (6 levels) to the evidence (modified GRADE). A multistep process for formulating, finalizing, reviewing and implementing the recommendations was completed [7,8].
• Royal College of Paediatrics and Child Health (RCPCH, 2017). This guideline, published online (343 references:1981-2017; 261 recommendations) is an update of the 2004 guideline [9]. Of the 261 recommendations, 83 were considered ‘key recommendations’. The authors acknowledged the lack of high quality evidence and used a formal Delphi consensus method to craft recommendations. The authors have created a ‘gold standard’ for pediatric stroke management from acute presentation through rehabilitation.
• Australian Childhood Stroke Advisory Committee (ACSAC, 2018). This guideline, published in an abbreviated version [10] as well as a more comprehensive online version [11] (349 references:1992-2017; 60+ recommendations) used a PICO format, SIGN methodology and the NHMRC system to screen and classify evidence, and then the GRADE system to make strong or weak recommendations. The final recommendations were reviewed by all committee members and underwent external review. A consensus process modified the final recommendations, made to assist prehospital and acute management. Recommendations were categorized as consensus-based recommendations (CBRs), adult-based or GRADE-based.
• AHA/ASA Scientific Statement (2018). The current statement (513 references:1969-2018; 60 recommendations) provides ‘considerations for clinical practice’ (i.e., recommendations) and identifies ‘controversies in current practice’ as well as ‘knowledge gaps’ [1]. Recommendations were made by group discussion. Several sections labeled ‘management’ in which recommendations for care are given separately from those listed under ‘considerations’. A common practice in this scientific statement as in many others (because of lack of evidence) is to describe current practices for different clinical situations.

Moving the field forward

Pediatric stroke has substantial potential to take advantage of the gains made in the developmental neurosciences, particularly the realization that because injury evolves over days to weeks, delayed treatments may impact long-term recovery. Recovery potential may be greater in the developing brain which is assumed to have greater ischemic ‘resilience’ and that developmental neuroplasticity occurs over years if not decades.

Pediatric stroke is rare but impairments are long-term

Approximately 5,100 pediatric strokes (AIS, ~3,000; CSVT, ~500; ICH, ~1,600) occur annually in the United States compared to 795,000 in adults. However, the average age of occurrence for all 3 entities (based on IPSS data) is about ~4-6 years and assuming that about 40+% of pediatric patients have life-long disability and that the life expectancy is ~60+ years, the number of ‘quality of life years’ of impairment in children is significant. In adults, nearly 75% of strokes occur over age 65, 40% have moderate to severe disability and 75% die within 7 years. Such estimates suggest that the life-long burden of pediatric stroke is disproportionately high and is a critical factor to consider when deciding on investing in research and care of these children.

Pediatric stroke encompasses 3 distinct clinical entities; should each require its own guideline?

The term pediatric stroke is one of convenience and it might be more advantageous to discuss AIS, CSVT and ICH as distinct entities rather than in one umbrella guideline which typically contains encyclopedic amounts of information that are difficult to digest, disseminate and revise. This is a common dilemma in guideline development. The 2017 RCPCH guideline is a good example. It demonstrated the value of bundling everything together (261 recommendations), making it more accessible as a unifying source of information, yet one wonders if it would have been less daunting to have the material divided by disease type or by the chronological stage of presentation (emergent, hospital, rehabilitative, etc). This is a judgment call based on a guideline committee’s vision, mission and capacity.

A related issue is how often guidelines should be updated, revised or retired. These also are difficult decisions as guidelines are costly, time consuming, labor intensive, and competitive in prioritizing topics. It is interesting to observe how guideline methodologies have become increasingly sophisticated and objective, yet alternative strategies also have been developed to provide consensus-based recommendations when there is insufficient evidence. The trend now is to at least have the process of consensus-based recommendations utilize systematic methods. Each discipline’s approach to this problem evolves depending on how useful a society’s members find the information. As outlined in their June 2010 process manual, the AHA has an exemplary approach [5]. Their guidelines are reviewed for possible updates one year after publication and yearly thereafter. Criteria for either a ‘focused update’ or a ‘revision/new guideline’ are described and a full revision occurs when there have been at least two previous focused updates, enough new evidence, or compelling reasons to change the scope or focus. The current statement comes on the heels of the British and Australian publications; the combined efforts demonstrate the acknowledgement that pediatric stroke evaluation and treatment deserves an increased investment of resources to develop solid scientific rationales for care.

Training and workforce issues, access to care and clinical trials

There are fundamental issues related to training/workforce needs, access to care and implementation of clinical trials that dramatically impact shifting the current clinical and research environment. Although we never will have the sample size that adult stroke trials muster, we can, as appropriate, parlay their achievements to the world of pediatric stroke (e.g., thrombolytic therapy, hyperacute stroke protocols) and conduct smaller, focused pediatric stroke trials to address the needs of our patients.

Training/Workforce

In the United States, the 2018 Child Neurology National Residency Matching Program offered 129 positions of which 96.3% were filled indicating that there are few medical school graduates entering the field of child neurology to create a pipeline towards a career in pediatric stroke. According to October 2018 IPSS data, there are only 16 programs worldwide that offer training in pediatric stroke (US/Canada, 13; Chile, 2; France, 1). There likely are a few more, but this still reflects limitations in building a larger group of pediatric stroke specialists. The greatest barrier is funding for training. This only can be addressed at national governmental levels and will require advocacy groups to lobby for such changes. The International Alliance for Pediatric Stroke plays a role in this effort [12]. The AHA has shown support for developing the field of pediatric stroke by publishing this scientific statement as well as by developing pediatric-focused scientific sessions at its annual International Stroke Conference. Additional AHA efforts to advance pediatric stroke training could have major long-term impact, as could new training initiatives from the NINDS. In 2000, the NINDS sponsored a 2-day workshop on perinatal and childhood stroke [13]. Additional workshops to explore current issues and key areas of focus to advance the field would be worthwhile.

One additional topic relates to pediatric stroke fellowship training in programs that are adult stroke oriented but have a pediatric training component versus trying to develop a combined pediatric neurocritical care/stroke program. Presently, there is no consensus and little formal discussion of the pros and cons of any approach.

Access to care

There are 212 acute care children’s hospitals in the United States and approximately 16 in Canada. Fewer than 10% to 20% have pediatric stroke services. To address this problem, the focus should be on establishing an initiative mandating the goal that within the next decade all children’s hospitals should have a multidisciplinary pediatric stroke service that meets the emergent, urgent and chronic rehabilitative needs of these patients. Such an initiative will require multidisciplinary collaboration. One approach to move this forward is for the pediatric stroke community to align their goals with the pediatric neurocritical care, neurosurgery, rehabilitation medicine, developmental/behavioral and physical, occupational, and speech therapy communities. It also would help to view pediatric stroke as a neurodevelopmental disability as this has major implications for long-term patient care.

Clinical trials

To date, there have been a handful of NINDS funded studies. Many have been initiated by members of the IPSS and include establishing an ongoing pediatric stroke data base (2007), clinical classification of stroke (Ped-NIHSS, CASCADE), etiology (the vascular effects of infection in pediatric stroke, VIPS), and thrombolytic safety (thrombosis in pediatric stroke, TIPS). Funding also has been provided by the Pediatric Epilepsy Research Foundation (seizures and pediatric stroke. SIPS); the Canadian Auxilium Foundation supports the maintenance of the IPSS central facility (at the Hospital for Sick Children in Toronto). More funding is needed for pediatric stroke research.

Is it time to start a society for pediatric stroke?

I would say yes. It has happened in the past that a pediatric subspecialty sees the need to separate from its adult counterparts with the most relevant example being the formation of the Child Neurology Society in 1972 as a distinct society from the American Academy of Neurology and the American Neurological Association [14]. The volume of pediatric stroke research has increased dramatically over the past two decades (e.g., more than 9000 PUBMED citations for pediatric stroke). Also, the IPSS is an extremely vibrant organization. It formed the first international pediatric stroke registry, is a multinational network of more than 150 clinicians and scientists from over 95 centers across 27 countries and its registry has more than 6,000 patients. Its members have published 28 papers, with 7 in preparation. The IPSS leadership has promulgated an international vision for pediatric stroke to meet many needs and this would allow solving the dilemma of how to collect scientific information on a group of rare disorders that would improve pediatric stroke patient care. Such an effort will require the collegial support of many groups and is a worthwhile endeavor.