Jennifer Armstrong-Wells

Symptomatic Neonatal Arterial Ischemic Stroke: The International Pediatric Stroke Study

BACKGROUND: Neonatal arterial ischemic stroke (AIS) has emerged as a leading cause of perinatal brain injury, cerebral palsy, and lifelong disability. The pathogenesis is poorly understood, which limits the development of treatment and prevention strategies. Multicenter studies must define epidemiology, risk factors, treatment practices, and outcomes to advance clinical trials and improve the adverse outcomes suffered by most survivors. METHODS: The International Pediatric Stroke Study is a global research initiative of 149 coinvestigators (30 centers in 10 countries). Patients with clinical and neuroimaging confirmation of symptomatic neonatal AIS were enrolled (2003–2007). Standardized, Web-based data entry collected clinical presentations, risk factors, investigations, treatments, and early outcomes. We examined predictors of infarct characteristics and discharge outcome by using multivariate logistic regression. RESULTS: Two hundred forty-eight neonates were studied (57% male, 10% premature). Most of them presented with seizure (72%) and nonfocal neurologic signs (63%). MRI was completed for 92% of the infants, although <50% had vascular imaging. Infarcts preferentially involved the anterior circulation and left hemisphere and were multifocal in 30%. Maternal health and pregnancies were usually normal. Neonates often required resuscitation (30%) and had systemic illnesses (23%). Cardiac and prothrombotic abnormalities were identified in <20% of the infants. Antithrombotic treatment was uncommon (21%) and varied internationally. Half (49%) of the infants had deficits at discharge, and data on their long-term outcomes are pending. CONCLUSIONS: Newborns with AIS are often systemically sick, whereas their mothers are usually healthy. Definitive causes for most neonatal AISs have not been established, and large-scale case-control studies are required to understand pathogenesis if outcomes are to be improved.

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

Neurocognitive outcomes following neonatal encephalopathy.

Neonatal encephalopathy (NE) from perinatal asphyxia (PA) has long been recognized as an important cause of lasting motor impairment in term newborns. NE has also, more recently, been implicated as an important risk factor for cognitive and behavioral difficulties as these children age. Newborns with mild NE appear to have normal neurocognitive outcomes, while those survivors with severe NE tend to have profound impediments. Yet, newborns with moderate NE seem to exhibit a wide range of cognitive outcomes - regardless of motor function - making prognostication in these children difficult in the newborn period. Since deficits are often subtle and remote from the initial injury, cognitive impairment is likely underdiagnosed in survivors of moderate perinatal NE. Therefore, it is important for ongoing formal neuropsychological evaluation, as well as parental and teacher education, to help aid in the cognitive and behavioral rehabilitation resulting from NE and perinatal hypoxic-ischemic brain injury.

Multiple intracranial aneurysms and moyamoya disease associated with microcephalic osteodysplastic primordial dwarfism type II: surgical considerations: Report of 3 cases

Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a rare genetic syndrome characterized by extremely small stature and microcephaly, and is associated in 25% of patients with intracranial aneurysms and moyamoya disease. Although aneurysmal subarachnoid hemorrhage and stroke are leading causes of morbidity and death in these patients, MOPD II is rarely examined in the neurosurgical literature. The authors report their experience with 3 patients who presented with MOPD II, which includes a patient with 8 aneurysms (the most aneurysms reported in the literature), and the first report of a patient with both moyamoya disease and multiple aneurysms. The poor natural history of these lesions indicates aggressive microsurgical and/or endovascular therapy. Microsurgery, whether for aneurysm clip placement or extracranial-intracranial bypass, is challenging due to tight surgical corridors and diminutive arteries in these patients, but is technically feasible and strongly indicated when multiple aneurysms must be treated or cerebral revascularization is needed.

Pain During Mogen or PlastiBell Circumcision

Routine neonatal circumcision can be a painful procedure. Although analgesia for circumcision has been studied extensively, there are few studies comparing which surgical technique may be associated with the least pain and discomfort when carried out by pediatric trainees.OBJECTIVE: We studied two commonly used techniques for circumcision to determine which was associated with less pain and discomfort.STUDY DESIGN: In a randomized, prospective, but not blinded study, newborns were circumcised either by Mogen clamp or by PlastiBell. All received dorsal nerve blocks with lidocaine. Fifty-nine well, term, newborn infants at San Francisco General Hospital were studied from 1997 to 1998. Circumcisions were carried out mostly by interns and residents in family practice and pediatrics. Pain was assessed by measuring duration of the procedure and by a simple behavioral score done sequentially.RESULTS: Dorsal nerve blocks were judged to be fully effective in over 70% of cases. Neither Mogen nor PlastiBell was associated with greater pain per 3-minute time period, but the PlastiBell technique on average took nearly twice as long as the Mogen procedure (20 vs 12 minutes). We judged that 60% of the infants had pain or discomfort associated with the procedure that was excessive. Residents and interns universally preferred the Mogen technique over the PlastiBell because of the formers simplicity.CONCLUSION: During the procedure, Mogen circumcision is associated with less pain and discomfort, takes less time, and is preferred by trainees when compared with the PlastiBell.

Neonatal giant pial arteriovenous malformation: genesis or rapid enlargement in the third trimester

A neonate with congestive heart failure at birth due to a nearly holohemispheric pial arteriovenous malformation is described. This occurred despite a normal second trimester prenatal sonogram. Successful treatment of heart failure was achieved by embolization alone. This case demonstrates that hemodynamically significant lesions may arise later or enlarge more rapidly in utero than previously thought.

The Methylenetetrahydrofolate Reductase Polymorphism (MTHFR c.677C > T) and Elevated Plasma Homocysteine Levels in a U.S. Pediatric Population with Incident Thromboembolism

OBJECTIVE Elevated plasma homocysteine (tHcy) and the MTHFR c.677C>T variant have been postulated to increase the risk of venous thromboembolism (VTE), although mechanisms and implications to pediatrics remain incompletely understood. The objectives of this study were to determine the prevalences of elevated tHcy and MTHFR variant in a pediatric population with VTE or arterial ischemic stroke (AIS), and to determine associations with thrombus outcomes. STUDY DESIGN Subjects were enrolled in an institution-based prospective cohort of children with VTE or AIS. Inclusion criteria consisted of objectively confirmed thrombus, ≤21years at diagnosis, tHcy measured and MTHFR c.677C>T mutation analysis. Clinical and laboratory data were collected. Frequencies for elevated tHcy and MTHFR variant were compared with NHANES values for healthy US children and also between study groups (VTE vs AIS, provoked vs idiopathic) and by age. RESULTS The prevalences of hyperhomocysteinemia or MTHFR variant were not increased in comparison to NHANES. tHcy did not differ between those with wild-type MTHFR versus either c.677C>T heterozygotes or homozygotes. There was no association between tHcy or MTHFR variant and thrombus outcomes. CONCLUSION In this cohort of US children with VTE or AIS, neither the prevalence of hyperhomocysteinemia nor that of MTHFR variant was increased relative to reference values, and adverse thrombus outcomes were not definitively associated with either. While it is important to consider that milder forms of pyridoxine-responsive classical homocystinuria will be detected only by tHcy, we suggest that routine testing of MTHFR c.677C>T genotype as part of a thrombophilia evaluation in children with incident thromboembolism is not warranted until larger studies have been performed in order to establish or refute a link between MTHFR and adverse outcomes.

Arteriopathy, D-Dimer, and Risk of Poor Neurologic Outcome in Childhood-Onset Arterial Ischemic Stroke

OBJECTIVE To assess whether acute findings of cerebral arteriopathy, large infarct, and acutely elevated plasma D-dimer levels are independently prognostic of poor long-term neurologic outcome as measured at ≥ 1 year post-event in children with arterial ischemic stroke (AIS). STUDY DESIGN Sixty-one patients with childhood-onset (ie, >28 days of life) AIS were enrolled in a single-institution cohort study at Childrens Hospital Colorado between February 2006 and June 2011. Data on demographic and diagnostic characteristics, antithrombotic treatments, and outcomes were systematically collected. RESULTS Cerebral arteriopathy and D-dimer levels >500 ng/mL (a measure of coagulation activation) were identified acutely in 41% and 31% of the cohort, respectively. Anticoagulation was administered in the acute period post-event in 40% of the children, in the subacute period in 43%, and in the chronic period in 28%. When not receiving anticoagulation, patients were routinely treated with aspirin 2-5 mg/kg once daily for a minimum of 1 year. Death, major bleeding (including intracranial hemorrhage), and recurrent AIS were infrequent. The Pediatric Stroke Outcome Measure at 1 year demonstrated poor outcome in 54% of the children. Acute cerebral arteriopathy and elevated D-dimer level were identified as putative prognostic factors for poor outcome; after adjustment for D-dimer, arteriopathy was an independent prognostic indicator (OR, 19.0; 95% CI, 1.6-229.8; P = .02). CONCLUSION Arteriopathy and coagulation activation are highly prevalent in the acute period of childhood AIS. Although recurrent AIS and intracranial hemorrhage were infrequent in our cohort, one-half of children experienced a poor neurologic outcome at 1 year, the risk of which was increased by acute arteriopathy. Substantiation of these findings in multi-institutional cohort studies is warranted, toward risk stratification in childhood-onset AIS.

Diagnosis and acute management of perinatal arterial ischemic stroke

Perinatal arterial ischemic stroke (PAIS) can be an unrecognized cause of short- and long-term neurologic disability. Focal clonic seizure in the newborn period is the most common clinical presentation of PAIS. MRI is optimal in diagnosing PAIS; negative cranial ultrasound or CT does not rule out PAIS. Given the low rate of recurrence in combination with risk factors thought to be isolated to the maternal-fetal unit, anticoagulation or antiplatelet treatment is usually not recommended. The majority of newborns with PAIS do not go on to develop epilepsy, although further research is warranted in this area. Long-term morbidity, including motor, cognitive, and behavioral disabilities, can follow PAIS, necessitating early recognition, diagnosis, and therapy initiation.

Late Cytotoxic Edema in 2 Children With Hemiplegia: Hemiplegic Migraine or Stroke?

Hemiplegic migraine (HM) is a rare variant of migraine with aura, characterized by migrainous headache and fully reversible motor deficit within 24 hours. Both sporadic and familial forms of HMs are genetically heterogenous with little information on neuroimaging during and after acute attacks. We report 2 cases of children with presumed HM and late cytotoxic edema.