PEDIATRICS Vol. 120 No. 3 September 2007, pp. 609-616 (doi:10.1542/peds.2007-0336)
SPECIAL ARTICLE |
Ischemic Perinatal Stroke: Summary of a Workshop Sponsored by the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke
a National Institute of Child Health and Human Development
b National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
c Departments of Neurology and Pediatrics, University of California, San Francisco, California
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ABSTRACT |
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 TOP ABSTRACT TERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Ischemic perinatal stroke is a disorder associated with significant long-term neurologic morbidity. With an estimated incidence of 1 in 2300 to 5000 births, stroke is more likely to occur in the perinatal period than at any time in childhood. The incidence of ischemic perinatal stroke ranks second only to that of strokes in the elderly population. Although ischemic perinatal stroke is a well-recognized disorder, many aspects remain to be studied. There is no consensus on its terminology, definition, or classification. Several risk factors have been identified, but their precise roles in causing stroke are not well understood. There are no reliable predictors of ischemic perinatal stroke on which to base prevention or treatment strategies. To review these important issues and propose a research agenda, the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke convened a workshop in August 2006. This article provides a summary of the workshop.
Key Words: cerebral palsy • diseases of pregnancy • focal cerebral infarction • congenital hemiplegia • hypoxic ischemic encephalopathy • intracranial hemorrhage • newborn • porencephaly • seizures • thrombotic disorders
Abbreviations: IPS—ischemic perinatal stroke • CP—cerebral palsy • MCA—middle cerebral artery • NICHD—National Institute of Child Health and Human Development • NINDS—National Institute of Neurological Disorders and Stroke • PPIS—presumed perinatal ischemic stroke • CT—computed tomography • DWI—diffusion-weighted imaging
Strokes that occur in the perinatal period are not rare; in fact, the perinatal period ranks second only to adult age groups in the incidence of stroke. It is estimated that the incidence of ischemic perinatal stroke (IPS) ranges between 1 in 2300 to 1 in 5000 births1–8 and accounts for 30% of children affected with hemiplegic cerebral palsy (CP) who were born at term or late-preterm gestations.4 Thus, IPS is the leading known cause for CP.
IPS is slightly more frequent in boys and in black infants compared with white infants. The reasons for these differential risks are not known. The left middle cerebral artery (MCA) is the most common vessel involved, with the left cerebral hemisphere the most common region affected. Thus, congenital hemiplegia from IPS is seen more often on the right than the left limbs. Other long-term risks from IPS include seizure disorders and delayed or impaired language development. Although IPS is primarily a neurologic disorder, children with this condition require expertise from a number of specialties including neurology, neuroradiology, hematology, perinatal/neonatal medicine, genetics, general pediatrics, and developmental and rehabilitation medicine for assessment, treatment, and follow-up care.
Although IPS is common, much remains to be learned about it. To review this topic and establish a research agenda, the National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS) organized a workshop in August 2006. This article provides a summary of the workshop. Because many comprehensive reviews have been published,1–8 we focus on 4 key issues: terminology, definition, and classification; risk factors and their role in the causal pathway; diagnosis; and research priorities.
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TERMINOLOGY, DEFINITION, AND CLASSIFICATION |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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A variety of events during the perinatal period can lead to occlusion of cerebral arterial or venous structures with focal disruption of blood supply to the brain, which causes a "stroke." Because this workshop was about IPS, the most common variety of stroke in late-preterm and term infants, we did not focus our discussions on other conditions such as cerebral arteriovenous malformations, intraparenchymal, periventricular, and intraventricular hemorrhages, focal patterns of cerebral damage resulting from diffuse ischemia including watershed infarctions seen in infants with perinatal hypoxic ischemic encephalopathy, or periventricular leukomalacia of preterm infants.
Authors have used differing terminologies and definitions for both stroke and perinatal period, resulting in numerous terms to describe this condition. Some of the terms used include perinatal stroke,8–10 perinatal arterial stroke,11,12 perinatal and neonatal ischemic stroke,13 arterial ischemic stroke,14 fetal stroke,15 and presumed prenatal or perinatal arterial ischemic stroke.16
Adhering to a consistent terminology and definition, however, would enrich the quality of research. Therefore, we chose the term IPS and defined it as "a group of heterogeneous conditions in which there is focal disruption of cerebral blood flow secondary to arterial or cerebral venous thrombosis or embolization, between 20 weeks of fetal life through the 28th postnatal day, confirmed by neuroimaging or neuropathologic studies."
Because the timing of the vascular event leading to IPS is almost always unknown, it was suggested that the classification of IPS be based on the gestational or postnatal age at diagnosis. The suggested subcategories were (1) fetal ischemic stroke, diagnosed before birth by using fetal imaging methods or in stillbirths on the basis of neuropathologic examination, (2) neonatal ischemic stroke, diagnosed after birth and on or before the 28th postnatal day (including in preterm infants), and (3) presumed perinatal ischemic stroke (PPIS), diagnosed in infants >28 days of age in whom it is presumed (but not certain) that the ischemic event occurred sometime between the 20th week of fetal life through the 28th postnatal day.
Rationale for the Suggested Definition and Classification Scheme
The definition of "perinatal period" follows the standard used for compiling national perinatal statistics in the United States. The phrase "ischemic stroke" emphasizes that the nature of pathology is one of ischemia, most often from vascular (arterial or venous) thrombosis. Categorization based on the age at diagnosis implies that one knows only the age at which a stroke diagnosis has been made and that, in most cases, the gestational age at which the stroke occurred cannot be ascertained with any degree of certainty. The PPIS subcategory allows for the inclusion of cases diagnosed after the neonatal period, yet they are "presumed" (but not certain) to have occurred during the perinatal period.
It is further stressed that in all categories of IPS (including PPIS), the age at stroke cannot be established with any degree of certainty and can only be conjectured to have occurred between the 20th week of fetal life through the 28th postnatal day.
Limitations of the Suggested Definition and Classification
There are no uniformly accepted neuroimaging criteria for reliably differentiating vasoocclusive ischemic brain lesions from focal infarctions. Distinguishing hemorrhagic conversion of ischemic lesions from primary hemorrhage occurring in the normal brain may be impossible. Similarly, neuroimaging features during the evolution of IPS from acute to chronic stages have not been studied. The longer the interval between the vascular event and radiologic assessment, the greater would be the difficulty in establishing the timing of the infarction.
Even neuropathologic studies cannot always distinguish initially ischemic lesions from initially hemorrhagic lesions, especially if stroke occurred long before death. Venous infarcts are often hemorrhagic to begin with, and ischemic infarcts may become hemorrhagic after reperfusion. Moreover, a single patient may have many vascular pathologies. Mortality from IPS is rare, and the autopsy rates have been declining; thus, relying solely on neuropathology for the diagnosis of IPS can lead to an underestimation of IPS prevalence while overestimating its severe forms.
Other limitations of the proposal are the timing of the diagnosis: the current proposal for fetal stroke excludes vasoocclusive strokes that might occur before 20 weeks of gestation. However, little is known about such conditions, mostly because pathologic evaluations are rarely conducted in fetal deaths before 20 weeks. Patients with silent strokes that occur after the 28th day of age may manifest signs and symptoms later in infancy or childhood. With the current definition, one can erroneously diagnose PPIS in such infants, although their stroke occurred after the perinatal period.
The Special Case of IPS in the Preterm Infant
Diagnosis of ischemic stroke in preterm infants poses a special challenge, because other forms of vascular pathologies are more common in preterm infants. Moreover, diagnosis of vasoocclusive strokes may be difficult without expertise in interpreting neuroimaging studies. Almost all reports on IPS have focused on term or late-preterm (previously known as near-term) infants. However, Lee et al found that 15% of infants with IPS in a general population were born at <36 weeks of gestation.17–19 Using a hospital-based data set of >10 years, Benders et al19 identified arterial IPS in 31 infants born at <37 weeks of gestation. All diagnoses were made by using cranial ultrasound and confirmed by using MRI. In 25 (81%) patients, the stroke was found in the territory of the MCA. Twin-to-twin transfusion syndrome, hypoglycemia, and abnormal fetal heart patterns were found to be associated with IPS.
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RISK FACTORS FOR IPS AND THEIR ROLE IN THE CAUSAL PATHWAY |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Figure 1 shows the complex, multifactorial relationship of risk factors identified in cases of IPS.16,20–29 Despite their association, however, the causal pathways and the nature of their interactions leading to IPS are poorly understood. Therefore, the observed risk factors (Table 1) cannot be inferred as definitive etiologies of IPS. Most of these risk factors were derived from descriptive epidemiologic studies; thus, only tentative conclusions can be drawn about their causal relationship to IPS.
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Compared with strokes in other age groups, IPS has many unique features. The normal physiologic processes in pregnancy lead to hypercoagulability of the blood even in healthy women. Pregnancy, therefore, is considered to be a natural prothrombotic state, with as many as 67 per 100000 pregnant women developing cerebral infarctions.30 Increased proclivity for clot formation during pregnancy is secondary to accelerated platelet-vessel interaction related to various hemostatic factors, accelerated thrombin generation, and decreased thrombolysis. Although a number of inherited and acquired thrombophilias in the mother and/or the fetus (Table 2) can cause enhanced clot formation (in the maternal or fetal vasculature or in the uteroplacental unit), it should be stressed that an overwhelming majority of pregnant women with thrombophilia are healthy and have a very low incidence of stroke in their offspring.
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Thrombotic episodes on the fetal side of the placenta can potentially lead to an embolic phenomenon in the fetal brain because of the patency of the foramen ovale and the right-to-left direction of blood flow in the fetal ductus arterious. Some investigators have proposed that in patients with symptomatic IPS, screening be conducted for several prothrombotic defects as done in the pediatric cases of stroke noted in Table 2. However, the cost/benefit analysis of such evaluations in all cases of IPS has not been studied.
Endothelial disruption associated with preeclampsia can also function as a prothrombotic stimulus. Diffuse and increased expression of tissue factors and thrombin early in the fetal life seems to play multiple roles in cell proliferation, differentiation, and signaling, with the fetus maintaining a delicate equilibrium between bleeding and thrombosis. This balance may shift toward excessive thrombotic or bleeding tendency depending on which segment of the coagulation cascade is perturbed.
Other unique features of IPS include the proinflammatory status of pregnancy, which increases the potential for prothrombotic interactions between inflammatory and coagulation pathways. Superimposed infections can exacerbate these tendencies and promote thrombotic episodes in either maternal or fetal circulation, particularly when there is concomitant maternal or fetal thrombophilia.
Other conditions associated with increased IPS include fetal polycythemia, twin-to-twin transfusion syndrome, persistent pulmonary hypertension, prolonged maintenance of catheters in the systemic or umbilical vessels, congenital heart disease with right-to-left shunting, arteriovenous malformations, and dehydration. Some nonspecific factors associated with increased incidence of IPS are male gender, non-Hispanic black ethnicity, and maternal autoimmune conditions.
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DIAGNOSTIC ISSUES |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Newborn infants with stroke most often present with focal or generalized seizures and sometimes with apnea, hypotonia, or episodes of duskiness, irritability, and poor feeding. Neuroimaging studies remain the most important tools for the confirmatory diagnosis of IPS14,31–35 (Table 3).
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Although cranial ultrasound helps in detecting a stroke in the first few days of life, one may miss cerebral ischemic lesions, especially those that are located more anteriorly or posteriorly.32,33 Even with computed tomography (CT) one may also miss IPS lesions, especially small lesions, during the first 24 hours after infarction. Therefore, conventional T2-weighted MRI, magnetic resonance angiography, and diffusion-weighted imaging (DWI) remain the principal methods for establishing the diagnosis of IPS.34,35
The time between the onset of symptoms and MRI is crucial for establishing the diagnosis with these techniques. Because of the increased water content of the unmyelinated brain, compared with the mature brain, T2 findings in IPS can be subtle during the first several days. Many studies have confirmed that ischemic tissue in the newborn brain can be detected by using DWI with high sensitivity during the first 2 days after the appearance of the symptoms. DWI sensitivity declines after 5 days of the appearance of symptoms. However, as the lesions become less visible on DWI, they become more visible on the conventional T1- and T2-weighted MRI.14,31,34,35
Conventional T1- and T2-weighted MRI and DWI allows precise delineation of the arterial distribution of the lesions, which helps in differentiating IPS from watershed or other nonvasoocclusive ischemic lesions. MRI features also enable prognostication, especially of motor outcomes. Vascular ischemic lesions in the MCA distribution, which affect tissue in the hemisphere, the posterior limb of the internal capsule, and the basal ganglia (lenticulostriate vessels), tend to cause hemiplegia irrespective of the size of the infarct. Involvement of the cerebral peduncles seen on early DWI is also associated with the development of hemiplegia.34,35
Ancillary Studies
Evaluation for risk factors includes testing for prothrombotic conditions. However, there is no consensus on how many of these tests are to be performed in IPS cases. Some experts advocate routine testing of all close family members of pediatric patients with stroke, and in positive cases, the members of extended family are included. The cost/benefit ratio of such investigations (especially those listed in Table 2) and its utility in counseling parents of infants with IPS have not been studied.
Other ancillary investigations in patients with IPS include tests for congenital heart malformations, assessment of vascular anatomy (especially in the neck), and evaluation of thrombotic lesions in systemic vessels.36
Autopsy and Evaluation of the Placenta
An autopsy can be very useful in defining the timing and the evolution of the vascular event that led to stroke.37 A complete autopsy, including examination of the heart, aorta, extracranial vessels, placenta, and umbilical cord,38,39 is necessary for evaluation of potential sources of thromboemboli and systemic vascular abnormalities. During the neuropathologic examination, the status of the intracranial arterial and sinovenous systems, gyral abnormalities, and the vascular distribution of all cerebral lesions should be documented. Microscopic sections should include the core, penumbra, and margin of identified lesions, corresponding contralateral regions, and involved blood vessels. Macroscopic and microscopic examinations of the placenta and the umbilical cord need to be undertaken.
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CURRENT AND EVOLVING THERAPIES |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Several experimental therapies for IPS are being evaluated.40,41 However, at present, treatment of infants with IPS remains focused on symptom relief, and the roles of thrombolytic therapies being studied in adult strokes have yet to be tested in infants.
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LONG-TERM OUTCOME |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Many studies have been published on the long-term outcome of IPS survivors.42–51 However, accurate outcome data are difficult to summarize because of varying characteristics of the cohorts, definitions, measures, and the duration of follow-up. However, some broad conclusions can be drawn. Neurologic deficits or epilepsy occur in 50% to 75% of survivors, with sensorimotor deficits being the most common.2,11,16,43–51 IPS is the most identified cause of congenital hemiplegia.1,47 More than 80% of infants with PPIS have hemiparesis.2,11,16,49 Deficits in language, vision, cognition, and behavior occur in 20% to 60% of IPS survivors.11,16,44,49 In most infants with IPS, focal neurologic deficits tend to emerge after early infancy, and new deficits can continue to evolve over the several years of childhood. Thus, long-term follow-up with standardized measures are required, because IPS survivors tend to grow into their deficits, and the extent of disability is not fully appreciated until they reach school age.
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RESEARCH GAPS AND PRIORITIES |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Numerous research gaps were identified from epidemiology to therapy of IPS (Table 4). Often, available funds dictate the research priorities and agenda. However, 2 areas were considered as needing urgent attention by the research community and the funding agencies: (1) developing uniform standards and criteria for IPS diagnosis using neuroimaging methods and studying their changes over time and (2) developing consistent terminology and subcategorization with precise definitions.
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SUMMARY AND CONCLUSIONS |
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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Over the past decade, IPS has emerged as an important cause of brain injury in the perinatal period and remains a leading cause of CP. The timing of stroke in IPS can almost never be established with certainty. Much remains to be learned to decipher the causal pathways and interactions among the risk factors identified in the mother and her infant with IPS. Because IPS is a multifactorial disorder that spans many specialties, professional societies may need to develop strategies to educate health care workers to understand this condition and to help in planning multispecialty follow-up care.
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ACKNOWLEDGMENTS |
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We offer special thanks to Gabrielle deVeber, MD (Director, Children's Stroke Program Division of Neurology, Hospital for Sick Children, Toronto, Ontario, Canada) for her immense contributions to the field of pediatric stroke and child neurology. She also provided valuable suggestions during the preparation of this article. The organizers thank the Office of Rare Diseases at the National Institutes of Health (NIH) for supporting this workshop.
We thank all the following speakers, discussants, session moderators, and participants: Stephen Ashwal, MD (Loma Linda University School of Medicine, Loma Linda, CA), Taeun Chang, MD (Children's National Medical Center, Washington, DC), Jieli Chen, MD (Henry Ford Hospital, Detroit, MI), Anne Comi, MD (Kennedy Krieger Institute, Baltimore, MD), Frances Cowan, MD, PhD (Imperial College London, Hammersmith Hospital, London, United Kingdom), Linda de Vries, MD (Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, Netherlands), David Edwards, FMedSci (Imperial College London), Donna Ferriero, MD (University of California, San Francisco, CA), Pankaj Ganguly (National Heart, Lung, and Blood Institute, NIH, Bethesda, MD), Murray Goldstein, DO, MPH (United Cerebral Palsy Research and Educational Foundation, Bethesda, MD), Meredith Golomb, MD, MSC (Indiana University School of Medicine, Indianapolis, IN), Marjorie Grafe, MD, PhD (Oregon Health and Science University, Portland, OR), Pierre Gressens, MD, PhD (Hospital Robert Debre, Paris, France), Gary Hankins, MD (University of Texas Medical Branch, Galveston, TX), James Hanson, MD (NICHD, NIH, Bethesda, MD), Marcus Hermansen, MD, Dartmouth Medical School, Nashua, NH), Rosemary Higgins, MD (NICHD, NIH), Deborah Hirtz, MD (NINDS, NIH, Bethesda, MD), Jill Hunter, MBBS (Baylor College of Medicine, Texas Children's Hospital, Houston, TX), Rebecca Ichord, MD (Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA), John Ilekis, PhD (NICHD, NIH), Terrie Inder, MD, PhD (Washington University School of Medicine, St Louis Children's Hospital, St Louis, MO), Janna Journeycake, MD, University of Texas Southwestern Medical Center, Children's Medical Center Dallas, Dallas, TX), Gili Kenet, MD (Tel Aviv University, Sheba Medical Center, Tel HaShomer, Israel), Adam Kirton, MD (Hospital for Sick Children, Toronto, Ontario, Canada), Michael Kupferminc, MD (Lis Maternity Hospital Tel Aviv Sourasky Medical Center, Tel Aviv University, Givataim, Israel), Warren Lo, MD (Ohio State University School of Medicine, Columbus, OH), Charles Lockwood, MD (Yale University School of Medicine, New Haven, CT), John K. Lynch, DO, MPH (NINDS, NIH), Karin Nelson, MD (NINDS, NIH), Dwight Nissley, PhD (Children's Hemiplegia and Stroke Association and Gene Regulation and Chromosome Biology Laboratory/National Cancer Institute-Frederick, Frederick, MD), U. Nowak-Gottl, MD (University Children's Hospital, Munster, Germany), Mary Ellen Palko, MS (Children's Hemiplegia and Stroke Association and Gene Regulation and Chromosome Biology Laboratory/National Cancer Institute-Frederick), Nigel Paneth, MD, MPH (Michigan State University, East Lansing, MI), Steven Pavlakis, MD (Mount Sinai School of Medicine, Maimonides Infants and Children's Hospital, Brooklyn, NY), Jeffery Perlman, MBChB (Weill Cornell Medical College, New York, NY), Tonse N.K. Raju, MD, DCH (NICHD, NIH), Uma Reddy, MD, MPH (NICHD, NIH), Raymond Redline, MD (Case School of Medicine, Cleveland, OH), E. Steve Roach, MD (Ohio State University School of Medicine), Robert Silver, MD (University of Utah Health Sciences Center, Salt Lake City, UT), Faye Silverstein, MD (University of Michigan, Ann Arbor, MI), Catherine Spong, MD (NICHD, NIH), Ann Stark, MD (Baylor College of Medicine, Texas Children's Hospital), Marian Willinger, PhD (NICHD, NIH), and Yvonne Wu, MD, MPH (University of California, San Francisco, CA).
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FOOTNOTES |
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Accepted Apr 11, 2007.
Address correspondence to Tonse N.K. Raju, MD, DCH, 6100 Executive Blvd, Room 4B03, Bethesda, MD 20892. E-mail: rajut{at}mail.nih.gov
The authors have indicated they have no financial relationships relevant to this article to disclose.
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TOPABSTRACTTERMINOLOGY, DEFINITION, AND...RISK FACTORS FOR IPS...DIAGNOSTIC ISSUESCURRENT AND EVOLVING THERAPIESLONG-TERM OUTCOMERESEARCH GAPS AND PRIORITIESSUMMARY AND CONCLUSIONSREFERENCES |
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