Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study.

BACKGROUND AND PURPOSE: Childhood arteriopathies are rare but heterogenous, and difficult to diagnose and classify, especially by nonexperts. We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings. MATERIALS AND METHODS: The Vascular Effects of Infection in Pediatric Stroke (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection and focal cerebral arteriopathy-inflammatory type, which includes transient cerebral arteriopathy, Moyamoya disease, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype. RESULTS: Among 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya disease (n = 34) occurred mostly in children younger than 8 years of age; focal cerebral arteriopathy-inflammatory type (n = 25), in children 8-15 years of age; and dissection (n = 26), at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected the cervical arteries, while Moyamoya disease involved the supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of focal cerebral arteriopathy-inflammatory type but was present in <25% of patients with focal cerebral arteriopathy-inflammatory type; a small lenticulostriate distribution infarct was a more common predictor of focal cerebral arteriopathy-inflammatory type, present in 76%. It remained difficult to distinguish focal cerebral arteriopathy-inflammatory type from intracranial dissection of the anterior circulation. We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis. CONCLUSIONS: Childhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of focal cerebral arteriopathy of childhood.

Pediatric intracranial nongalenic pial arteriovenous fistulas: clinical features, angioarchitecture, and outcomes.

BACKGROUND AND PURPOSE: NGAVFs are rare vascular malformations usually presenting in infancy or childhood. We sought to identify clinical and angiographic predictors of clinical outcome for these lesions. MATERIALS AND METHODS: Retrospective review of a neurointerventional data base identified 386 pediatric patients with intracranial AVFs and AVMs, from which a cohort of 25 patients with NGAVF were selected for medical record and imaging analysis. RESULTS: NGAVFs constituted 7.3% of pediatric intracranial vascular lesions with a nondural arteriovenous shunt. Seven of 8 patients who presented in the first month of life had CHF and harbored large, complex fistulas with multiple sites of arteriovenous shunting. Single-hole fistulas predominated later in childhood and more frequently presented with seizures, hemorrhage, or focal neurologic deficits. More treatment procedures were performed in subjects presenting at ≤ 2 years of age compared with older children (median = 3 versus 2, P = .041), and in those harboring a multi-hole fistula versus those with a single-hole fistula (median = 3 versus 2, P = .003). Eighteen patients (72%) had complete posttreatment elimination of NGAVF shunting. Compared with patients presenting at >2 years of age, patients presenting in the first 2 years of life were more likely to have a multi-hole fistula (100% versus 25%, P = .0001) and to have a poor clinical outcome (54% versus 0%, P = .0052), defined as a pediatric mRS of ≥ 3. CONCLUSIONS: The morbidity of NGAVF appears higher than previously reported despite a somewhat higher rate of angiographic cure. Poor clinical outcome occurred primarily in patients with multi-hole NGAVFs presenting at ≤ 2 years of age.

Cervical and intracranial arterial anomalies in 70 patients with PHACE syndrome.

BACKGROUND AND PURPOSE: Cerebral and cervical arterial abnormalities are the most common non-cutaneous anomaly in PHACE syndrome, but the location and type of arterial lesions that occur have not been systematically assessed in a large cohort. Our aim was to characterize the phenotypic spectrum of arteriopathy, assess the frequency with which different arteries are involved, and evaluate spatial relationships between arteriopathy, brain structural lesions, and hemangiomas in PHACE syndrome. MATERIALS AND METHODS: Intracranial MRA and/or CTA images from 70 children and accompanying brain MR images in 59 patients with arteriopathy and PHACE syndrome were reviewed to identify the type and location of arterial lesions and brain abnormalities. Five categories of arteriopathy were identified and used for classification: dysgenesis, narrowing, nonvisualization, primitive embryonic carotid-vertebrobasilar connections, and anomalous arterial course or origin. Univariate logistic regression analyses were performed to test for associations between arteriopathy location, hemangiomas, and brain abnormalities. RESULTS: By study design, all patients had arterial abnormalities, and 57% had >1 form of arteriopathy. Dysgenesis was the most common abnormality (56%), followed by anomalous course and/or origin (47%), narrowing (39%), and nonvisualization (20%). Primitive embryonic carotid-vertebrobasilar connections were present in 20% of children. Hemangiomas were ipsilateral to arteriopathy in all but 1 case. The frontotemporal and/or mandibular facial segments were involved in 97% of cases, but no other specific associations between arteriopathy location and hemangioma sites were detected. All cases with posterior fossa anomalies had either ICA anomalies or persistent embryonic carotid-basilar connections. CONCLUSIONS: The arteriopathy of PHACE syndrome commonly involves the ICA and its embryonic branches, ipsilateral to the cutaneous hemangioma, with dysgenesis and abnormal arterial course the most commonly noted abnormalities. Brain abnormalities are also typically ipsilateral.

The 5-year direct medical cost of neonatal and childhood stroke in a population-based cohort.

BACKGROUND: Despite increasing awareness of the long-term impact of pediatric stroke, there are few estimates of the costs of care. We examined acute and 5-year direct costs of neonatal and childhood stroke in a population-based cohort in Northern California. METHODS: We obtained electronic cost data for 266 children with neurologist-confirmed strokes, and 786 age-matched stroke-free controls, within the population of all children (<20 years) enrolled in a large managed care plan from 1996 through 2003. Cost data included all inpatient and outpatient health service costs including care at out-of-plan facilities. Costs were assessed for 5 years after stroke, expressed in 2003 US dollars, and stratified by age at stroke onset (neonatal, defined as <29 days of life, vs childhood). Stroke costs were adjusted for costs in stroke-free age-matched controls. RESULTS: Average adjusted 5-year costs for pediatric stroke are substantial: $51,719 for neonatal stroke and $135,161 for childhood stroke. The average cost of a childhood stroke admission was $81,869. The average birth admission cost for a neonatal stroke was $39,613; adjustment for control birth admission costs reduced this by only $4,792, suggesting the stroke accounted for 88% of costs. Even among neonates whose strokes were not recognized until later in childhood ("presumed perinatal strokes"), admission costs exceeded those of controls. Chronic costs were highest in the first year poststroke, but continued to exceed control costs even in the fifth year by an average of $2,016. CONCLUSIONS: The economic burden of neonatal and childhood stroke is both large and sustained.

Utilization of TCD screening for primary stroke prevention in children with sickle cell disease.

BACKGROUND: In 1998, the Stroke Prevention Trial in Sickle Cell Anemia showed a >90% reduction in stroke rates after blood transfusion therapy in children with sickle cell disease (SCD) identified as high risk with transcranial Doppler ultrasonography (TCD) screening. METHODS: We studied the utilization of TCD screening in a retrospective cohort of all children with SCD within a large managed care plan from January 1993 to December 2005. Rates of first TCD screening were estimated using life table methods; predictors of TCD were evaluated using Cox proportional hazards regression. Stroke incidence rates were estimated in person-time before (pre-TCD) and after (post-TCD) first TCD. RESULTS: The average annual rate of TCD screening in 157 children with SCD was 1.8 per 100 person-years pre-1998, 5.0 from January 1, 1998, to December 31, 1999, and 11.4 after 1999. The only independent predictor of TCD screening was proximity to the vascular laboratory. The annualized stroke rate pre-TCD was 0.44 per 100 person-years, compared to 0.19 post-TCD. CONCLUSIONS: Since the Stroke Prevention Trial in Sickle Cell Anemia, the rate of transcranial Doppler ultrasonography (TCD) screening in sickle cell disease (SCD) has increased sixfold within a large health care plan. Children living farther from a vascular laboratory are less likely to be screened. Increased availability of TCD screening could improve the utilization of this effective primary stroke prevention strategy.

Intracranial aneurysms in childhood: 27-year single-institution experience.

BACKGROUND AND PURPOSE: Pediatric aneurysms are rare and, thus, relatively poorly understood as compared to those in adults. Our aim was to characterize the clinical, imaging, treatment, and outcome data of patients younger than 19 years diagnosed with intracranial aneurysms at a tertiary care institution. MATERIALS AND METHODS: We performed a retrospective medical record review of pediatric patients examined at our university hospital between 1981 and 2008. RESULTS: We evaluated 77 patients (mean age, 12 years; 40 female, 37 male) with 103 intracranial aneurysms. Patients presented with headache (45%), cranial neuropathies (16%), nausea/vomiting (15%), vision changes (13%), trauma (13%), seizure (4%), or sensory changes (3%). Subarachnoid hemorrhage occurred in 25 patients. Thirty-one fusiform aneurysms occurred in 25 patients. Forty-seven saccular aneurysms occurred in 35 patients. Twelve infectious aneurysms occurred in 6 patients. Fifteen traumatic aneurysms occurred in 12 patients. Fifty-nine patients underwent treatment of their aneurysms; 18 patients' conditions were managed conservatively. Nineteen patients underwent primary endovascular coiling, 1 patient had endovascular stent-assisted coiling, 11 patients underwent endovascular parent artery occlusion, 19 patients underwent surgical clipping, and 10 patients had aneurysms trapped and bypassed. Mortality was 1.3%. Morbidity included 8% infarction and 4% new-onset seizures. Six patients developed new aneurysms or had enlargement of untreated aneurysms. CONCLUSIONS: In our experience, intracranial aneurysms of childhood show a female predilection and predominantly saccular morphology. In neurovascular centers where microneurosurgical and endovascular options are available, most children with intracranial aneurysms can be successfully treated with low morbidity and mortality. Fusiform aneurysms require a combined microneurosurgical and endovascular approach more often than saccular aneurysms. The development of new aneurysms in pediatric patients during limited follow-up warrants further investigation.

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.

Neurodevelopmental outcome after endovascular treatment of vein of Galen malformations.

OBJECTIVE: To assess neurodevelopmental outcome after endovascular treatment of vein of Galen malformations (VOGM). METHODS: Outcome of patients who underwent endovascular treatment for VOGM between 1983 and 2002 was assessed by chart review and parental questionnaires. Development was classified as normal, minor delay (slow initial acquisition of milestones but no permanent disability), or significant delay (slow or incomplete acquisition of milestones with some permanent disability) using an adaptation of the Denver Developmental Questionnaire. RESULTS: Twenty-seven patients were identified: five presented prenatally (by ultrasound), 16 as neonates, and 6 after the neonatal period. The most common presenting features were congestive heart failure (CHF; 16/27) and hydrocephalus (8/27). The 16 patients with CHF all presented either prenatally or neonatally; 4 died acutely, 6 had significant delay, and 6 had no or minor developmental delay. Of those presenting in the perinatal period without CHF, all survived, two of five were significantly delayed, and three of five had no delay. Of those presenting after the neonatal period, all survived and only one of six had delay. By angiographic classification, outcome was worse for those with choroidal VOGM (3/13 died; 5/13 had significant delay) than for those with mural VOGM (2/10 had significant delay; none died). For the entire series, 52% of all cases (61% of survivors) had no or minor delay. CONCLUSIONS: Fourteen of 27 children who received treatment for VOGM had a favorable outcome. Features associated with worse outcome were perinatal presentation, presence of CHF, and choroidal angioarchitecture.

Deaths from stroke in US children, 1979 to 1998.

BACKGROUND: Studies have documented declining mortality from stroke in adults over the past two decades, with black adults at greater risk of death from stroke than whites in all years. As these findings have been attributed to control of stroke risk factors that are less important in children, trends and demographics of childhood stroke mortality are of interest, but have not been explored. METHODS: The authors analyzed death certificate data for ischemic and hemorrhagic stroke (subarachnoid hemorrhage [SAH] and intracerebral hemorrhage [ICH]) in children under 20 years of age in the United States for the years 1979 through 1998, covering approximately 1.5 billion person-years. RESULTS: Childhood mortality from stroke declined by 58% overall, with reductions in all major subtypes (ischemic stroke decreased by 19%; SAH, by 79%; ICH, by 54%). Black ethnicity was a risk factor for mortality from all stroke types (relative risk 1.74 for ischemic stroke; 1.76 for SAH; 2.06 for ICH; p < 0.0001 for all types). Male sex was a risk factor for mortality from SAH (relative risk 1.30, p < 0.0001) and ICH (relative risk 1.21, p < 0.0001), but not from ischemic stroke (relative risk 1.02, p = 0.76). CONCLUSIONS: Mortality from stroke in US children has decreased dramatically over the last 20 years. Black children are at greater risk of death from all stroke types than are white children. As control of known stroke risk factors is unlikely to account for declining stroke mortality and ethnic differences in children, unrecognized stroke risk factors may be important.

Arterial dissection and stroke in children.

OBJECTIVE: To describe the clinical characteristics of dissections of cerebral arteries in children. METHODS: Searches of MEDLINE (1966-2000) and bibliographies were systematically performed for English-language publications that described patients <18 years old with anterior circulation arterial dissections (ACAD) or posterior circulation arterial dissections (PCAD). RESULTS: A total of 2,027 studies were reviewed; 118 patients were identified in 79 studies. Seventy-four percent of patients with ACAD (n = 73) and 87% with PCAD (n = 47) were male (p < 0.0001). When patients with preceding trauma were excluded, this male predominance persisted. All patients had evidence of cerebral ischemia at the time of diagnosis. Headache was reported in approximately half of patients. Sixty percent of ACAD were intracranial. ACAD with no preceding trauma were more commonly intracranial than those preceded by significant trauma (86 vs 25%, p = 0.002). The most common location for PCAD was the vertebral artery at the level of the C1-C2 vertebral bodies (53%). Recurrent ischemic events after the diagnosis of dissection were reported in 15% of PCAD and 5% of ACAD cases. None of the PCAD group and 10% of the ACAD group had recurrent dissections. CONCLUSIONS: There is a marked male predominance among children with cerebral arterial dissections that is not explained by trauma. Unlike adult ACAD, childhood ACAD are most commonly intracranial. Spontaneous ACAD, in particular, tend to be intracranial, while post-traumatic ACAD are more often extracranial. The vertebral artery segment most susceptible to dissection is similar between children and adults.

Copper/zinc superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia.

Unlike the mature animal, immature mice transgenic for copper/zinc superoxide dismutase (SOD1) have greater brain injury after hypoxia-ischemia than their wild-type nontransgenic littermates. To assess the role of oxidative stress in the pathogenesis of this injury, we measured histopathological damage, lipid peroxidation products, enzymatic activities of catalase and glutathione peroxidase, and hydrogen peroxide (H2O2) concentration in these animals before and after hypoxic-ischemic injury. Lipid peroxidation products were significantly increased 2 hours after the insult in both transgenic and nontransgenic brains in hippocampus, the most damaged brain region. Catalase activity did not increase in response to SOD1 overexpression or injury in either group. However, glutathione peroxidase activity, unchanged in response to overexpression, decreased significantly 24 hours after injury in both groups. At 24 hours after injury, greater H2O2 accumulation was observed in transgenic brains. Because SOD1 dismutates superoxide to H2O2, overexpression of SOD1 in the presence of developmentally low activities of the catalytic enzymes glutathione peroxidase and catalase leads to an increased production of H2O2, and may explain the increased brain injury observed after hypoxia-ischemia in neonatal SOD1 mice.

Proton magnetic resonance relaxation behavior of whole muscle with fatty inclusions.

This in vitro proton study of spin lattice (T1) and spin spin (T2) relaxation of muscle with storage-fat inclusions demonstrates slow exchange and lack of cross-relaxation between fat and water. Slow exchange causes biphasic T1 relaxation, but T2 relaxation is paradoxically uniphasic due to the nearly equal T2 values for both fractions. By careful dehydration and fat extraction, the relaxation information was deconvolved into water, fat, and protein contributions. The biphasic T1 decay has a short component due to lipid and a long component due to the water-protein combination. The fat content of muscle can be measured from the relative amplitude of the two T1 components or directly from the T2 relaxation time.