The Stress Phenotyping Framework: A multidisciplinary biobehavioral approach for assessing and therapeutically targeting maladaptive stress physiology.

Although dysregulated stress biology is becoming increasingly recognized as a key driver of lifelong disparities in chronic disease, we presently have no validated biomarkers of toxic stress physiology; no biological, behavioral, or cognitive treatments specifically focused on normalizing toxic stress processes; and no agreed-upon guidelines for treating stress in the clinic or evaluating the efficacy of interventions that seek to reduce toxic stress and improve human functioning. We address these critical issues by (a) systematically describing key systems and mechanisms that are dysregulated by stress; (b) summarizing indicators, biomarkers, and instruments for assessing stress response systems; and (c) highlighting therapeutic approaches that can be used to normalize stress-related biopsychosocial functioning. We also present a novel multidisciplinary Stress Phenotyping Framework that can bring stress researchers and clinicians one step closer to realizing the goal of using precision medicine-based approaches to prevent and treat stress-associated health problems.

Wired for Threat: Clinical Features of Nervous System Dysregulation in 80 Children.

BACKGROUND: The negative effect of perceived stress on health has become a cultural epidemic. Despite many health implications, the clinical impact of stress on the nervous system is not well understood. This case series describes the symptom profiles of 80 children with nervous system dysregulation attributed to maladaptive neuroendocrine responses to stress. METHODS: We reviewed of 80 children with nervous system dysregulation identified from a single, tertiary care pediatric neurology clinic. Included patients were between five and 17 years of age, with unexplained medical symptoms lasting three months or longer affecting at least four of six neurological domains: (1) somatization, (2) executive function, (3) autonomic function, (4) digestion, (5) sleep, and (6) emotional regulation. Medical symptoms, diagnoses, and detailed social histories were collected. RESULTS: Of 80 children, 57 were female (71%), 57 were Caucasian (71%), with median age of 14 years. Symptoms had a mean duration of 32 months, and included: 100% somatic symptoms, 100% emotional dysregulation, 92.5% disrupted sleep, 82.5% autonomic dysregulation, 75% executive dysfunction, and 66% digestive problems. Overall, 94% reported chronic or traumatic stressors; adverse childhood experiences were present in 65%. CONCLUSIONS: Perceived stress impacts many functions of the neuroendocrine system through experience-dependent plasticity, resulting in a constellation of symptoms and functional impairments we describe as nervous system dysregulation. The pathophysiology of these symptoms involves dysregulation of subcortical, hormonal, and autonomic circuits, which remain largely untested. Recognition and understanding of maladaptive neurophysiology in stress-related symptoms has important implications for diagnosis, treatment, and advances in health research.

Arterial Wall Imaging in Pediatric Stroke.

BACKGROUND AND PURPOSE: Arteriopathy is common in childhood arterial ischemic stroke (AIS) and predicts stroke recurrence. Currently available vascular imaging techniques mainly image the arterial lumen rather than the vessel wall and have a limited ability to differentiate among common arteriopathies. We aimed to investigate the value of a magnetic resonance imaging-based technique, namely noninvasive arterial wall imaging (AWI), for distinguishing among arteriopathy subtypes in a consecutive cohort of children presenting with AIS. METHODS: Children with confirmed AIS and magnetic resonance angiography underwent 3-Tesla AWI including T1-weighted 2-dimensional fluid-attenuated inversion recovery fast spin echo sequences pre- and post-gadolinium contrast. AWI characteristics, including wall enhancement, wall thickening, and luminal stenosis, were documented for all. RESULTS: Twenty-six children with AIS had AWI. Of these, 9 (35%) had AWI enhancement. AWI enhancement was associated with anterior circulation magnetic resonance angiography abnormality and cortical infarction in 8 of 9 (89%) children and normal magnetic resonance angiography with posterior circulation subcortical infarction in 1 (1 of 9; 11%) child. AWI enhancement was not seen in 17 (65%), 10 (59%) of whom had an abnormal magnetic resonance angiography. Distinct patterns of pre- and postcontrast signal abnormality were demonstrated in the vessel wall in the region of interest in children with transient cerebral arteriopathy, arterial dissection, primary central nervous system angiitis, dissecting aneurysm, and cardioembolic stroke. CONCLUSIONS: AWI is a noninvasive, high-resolution magnetic resonance AWI technique, which can be successfully used in children presenting with AIS. Patterns of AWI enhancement are recognizable and associated with specific AIS pathogeneses. Further studies are required to assess the additional diagnostic utility of AWI over routine vascular imaging techniques, in childhood AIS.

The Utility of Collaterals as a Biomarker in Pediatric Unilateral Intracranial Arteriopathy.

BACKGROUND: Intracranial arteriopathies are frequent causes of pediatric stroke and important risk factors for stroke recurrence. Without tissue diagnosis, vascular imaging is relied upon to identify the underlying etiology and prognosis. We hypothesized that children with unilateral intracranial arteriopathy with lenticulostriate collaterals would demonstrate distinct vascular outcomes compared with children without collaterals. METHODS: We retrospectively identified children with unilateral intracranial arteriopathy from two institutions. Two blinded raters from each institution reviewed magnetic resonance or digital subtraction angiography at baseline and ≥12 months. Patients were grouped according to presence or absence of lenticulostriate collaterals. Clinical features and vascular imaging outcomes were compared using univariate analysis and multivariate logistic regression. RESULTS: Forty-four children were included: 22 males, median age 8.2 years (range two to 16.9 years), and further stratified into the collateral group (n = 20) and non-collateral group (n = 24), with median follow-up of 25.5 months and 23 months, respectively. Both groups demonstrated similar rates of progression on vascular imaging at ≥12 months, 50% in the collateral group versus 37.5% in the non-collateral group (P > 0.05). The collateral group was associated with asymptomatic clinical presentation, normal brain MRI, border zone infarcts, and either vascular stabilization or new contralateral disease. The non-collateral group demonstrated either vascular improvement or discordant progression (combination of improved and progressive lesions). Using a multivariate model, collaterals continued to be an independent predictor of vascular outcome. CONCLUSIONS: This study suggests that lenticulostriate collaterals in children with unilateral intracranial arteriopathy may serve as a useful neuroimaging biomarker that helps to stratify patients with distinct clinical features and patterns of vascular evolution.

Clinical Profile Associated with Adverse Childhood Experiences: The Advent of Nervous System Dysregulation.

BACKGROUND: We report the prevalence of children with multiple medical symptoms in a pediatric neurology clinic, describe their symptom profiles, and explore their association with adverse childhood experiences (ACEs). METHODS: We retrospectively reviewed 100 consecutive patients from an outpatient pediatric neurology clinic. Patients were included if they were ≥5 years old and reported ≥4 symptoms that were unexplained for ≥3-months. Symptom profiles across six functional domains were recorded: (1) executive dysfunction, (2) sleep disturbances, (3) autonomic dysregulation, (4) somatization, (5) digestive symptoms, and (6) emotional dysregulation. ACEs were scored for all patients. RESULTS: Seventeen patients reported ≥4 medical symptoms. Somatization, sleep disturbances, and emotional dysregulation occurred in 100% patients, with executive dysfunction (94%), autonomic dysregulation (76%), and digestive problems (71%) in the majority. Forty-two children reported ≥1 ACE, but children with ≥4 symptoms were more likely to report ACEs compared to other children (88% vs. 33%; p < 0.0001) and had a higher median total ACE score (3 vs. 1; p < 0.001). CONCLUSIONS: Children with multiple medical symptoms should be screened for potential exposure to ACEs. A clinical profile of symptoms across multiple functional domains suggests putative neurobiological mechanisms involving stress and nervous system dysregulation that require further study.

Moyamoya Disease in Children: Results From the International Pediatric Stroke Study.

This study aimed to describe children with moyamoya disease from an international multicenter stroke database, and explore risk factors for stroke recurrence. We reviewed data of children >28-days old with moyamoya disease enrolled in the International Pediatric Stroke Study from January 2003 to March 2013. A total of 174 children from 32 sites and 14 countries had moyamoya disease; median age 7.4 years, 49% male. Of these, 90% presented with ischemic stroke, 7.5% with transient ischemic attack, and 2.5% with hemorrhagic stroke. One-third of patients had moyamoya syndrome. Stroke recurrence was 20% over median follow-up of 13 months; 9% had multiple recurrences. Children treated with surgical revascularization were less likely to have stroke recurrence ( P = .046). Moyamoya disease accounted for 8% of arterial strokes in this international pediatric stroke registry. One-third of pediatric patients with moyamoya disease have an underlying syndromic condition. Surgical revascularization is effective at reducing the incidence of stroke recurrence.

Subacute Sclerosing Panencephalitis: The Foothold in Undervaccination.

Subacute sclerosing panencephalitis (SSPE) is a fatal complication of measles infection. We present a case of a fully vaccinated 3-year-old boy who was diagnosed with and treated for autoimmune encephalitis before arriving at a diagnosis of SSPE. We discuss the challenges of diagnosing SSPE in developed countries.

Vascular Imaging Outcomes of Childhood Primary Angiitis of the Central Nervous System.

BACKGROUND: Inflammation affecting cerebral blood vessels is a common cause of stroke in children. Arterial abnormalities on vascular imaging are an important risk factor for stroke recurrence. We aimed to describe the vascular imaging outcomes in children with primary angiitis of the central nervous system after 12 months and identify factors associated with vascular progression and stroke recurrence. METHODS: We retrospectively analyzed clinical and neuroimaging data from the BrainWorks Registry of children with large-vessel primary angiitis of the central nervous system. Neuroimaging was collected at baseline and at least 12-month follow-up, and vascular outcome was categorized as improved, stable, or progressed based on comparison of magnetic resonance angiography. Univariate clinical and neuroimaging predictors were associated with outcome by Fisher exact test. RESULTS: Our study consisted of 27 children; 20 male; median age was 7.92 years (range, two to 15 years). Twelve patients received steroids (44%). Median follow-up time was 16 months (range, 12 to 56 months). Vascular imaging outcome was categorized as improved in 37%, stable in 22%, and progressed in 41% of patients. Discordant progression, defined as progression and improvement occurring simultaneously across multiple vessels, was observed in 26%. Stroke recurred in 15%, occurring exclusively in the group with progression on follow-up imaging (P = 0.02). CONCLUSIONS: After 12 months, 40% of children with primary angiitis of the central nervous system demonstrated progression on vascular imaging, without apparent clinical or angiographic predictors. Stroke recurrence was associated with vascular progression. Discordant progression is a newly described angiographic finding. Further studies are necessary to determine if this represents a unique characteristic of inflammatory arteriopathies.

Quality of Life in Pediatric Moyamoya Disease.

BACKGROUND: Moyamoya disease (MMD) is a progressive intracranial arteriopathy with high risk of stroke. Its impact on quality of life is unstudied. We surveyed children with moyamoya disease and compared their quality of life to chronically ill children and children with stroke to better understand the impact of this diagnosis. METHODS: Children with moyamoya disease aged seven to 17 years from Stanford's Moyamoya Clinic between June 2014 and March 2015 were included. Children with syndromic neurodevelopmental diagnoses were excluded. Patients were surveyed using the Pediatric Quality of Life 4.0, in addition to the Pediatric Stroke Outcome Measure or Recovery Recurrence Questionnaire. Mean scores were compared to normative data sets. Linear regression models compared total quality of life scores in patients with and without stroke, after adjusting for confounders. RESULTS: This cross-sectional study included 30 children with moyamoya disease; ten were male, and the median age was 13.5 years (range, 7 to 17 years). Twenty children (67%) had a stroke, and 14 of these had good neurological outcome (70%). Mean parent-proxy Pediatric Quality of Life scores were lower in all domains compared to healthy controls (P < 0.05), and all scores were comparable to chronically ill children and children with non-moyamoya disease stroke. There was no significant difference in total quality of life between patients with and without stroke. CONCLUSIONS: Even in the absence of stroke, children with moyamoya disease have lower quality of life than healthy controls and a similar quality of life to chronically ill children and those with non-moyamoya disease stroke. Children with moyamoya disease would benefit from mental health support beyond what a mild physical presentation may indicate.

Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm.

A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral artery (PCA) aneurysm. This aneurysm was successfully treated by endovascular coil sacrifice of the affected segment of the PCA. The patient made an excellent recovery with no significant residual neurologic deficit.

Focal Cerebral Arteriopathy: The Face With Many Names.

OBJECTIVE: Focal cerebral arteriopathy is a term used to describe unilateral intracranial arteriopathy involving the distal internal carotid artery and proximal segments of the middle and anterior cerebral artery. We describe the disease course of 10 pediatric arterial ischemic stroke patients with focal cerebral arteriopathy from a single quaternary-care center. METHODS: We retrospectively reviewed pediatric stroke patients with focal cerebral arteriopathy without lenticulostriate collaterals treated at our institution between 2005 and 2014. Angiography was reviewed by a child neurologist and a pediatric neuroradiologist, and chart reviews were performed. RESULTS: Ten individuals with focal cerebral arteriopathy were identified. At the time of stroke presentation, four patients were diagnosed with arterial dissection, two with moyamoya disease, one with embolic occlusion, one with hemorrhagic stroke, and two with arterial dissection or vasculitis. At last follow-up, six patients had a change in diagnosis: four were diagnosed with transient cerebral arteriopathy, two with arterial dissection, and four with moyamoya disease. Four children experienced stroke recurrence. All were administered aspirin, one was administered heparin, two were administered intravenous tissue plasminogen activator, and five underwent surgical revascularization. CONCLUSIONS: Among pediatric stroke patients with a similar angiographic appearance, there is variable concordance between diagnosis, prognosis and treatment choice. Improved consensus-based diagnostic criteria and further research is needed to identify disease biomarkers and predictors of arterial progression.

Cerebral vascular findings in PAPA syndrome: cerebral arterial vasculopathy or vasculitis and a posterior cerebral artery dissecting aneurysm.

A young patient with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome developed an unusual cerebral arterial vasculopathy/vasculitis (CAV) that resulted in subarachnoid hemorrhage from a ruptured dissecting posterior cerebral artery (PCA) aneurysm. This aneurysm was successfully treated by endovascular coil sacrifice of the affected segment of the PCA. The patient made an excellent recovery with no significant residual neurologic deficit.

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.

Long-term outcomes of pediatric ischemic stroke in adulthood.

This population-based study assesses the long-term impact of childhood stroke on function and independence in young adults. We undertook a cross-sectional outcome study of patients with arterial ischemic stroke and cerebral sinovenous thrombosis, beyond 18 years of age. We studied 26 patients; 21 arterial stroke, 5 cerebral sinovenous thrombosis, with 16 females. Mean age at assessment was 21.5 years, and mean follow-up time was 10.8 years. According to the modified Rankin Scale, final outcomes were 37% normal, 42% mild, 8% moderate, and 15% severe deficits. Risk factors for abnormal functional outcome included arterial ischemic stroke, presence of arteriopathy, and 1-year poststroke Pediatric Stroke Outcome Measure score ≥ 2 (P < .05). Most (77-84%) were independent in driving, relationships, and employment. Functional status at 1 year poststroke strongly predicts long-term outcome. Mental illness in one-quarter of young adults surviving childhood stroke represents an important direction for research.

Placental pathology in neonatal stroke.

OBJECTIVE: Neonatal stroke is increasingly recognized, and risk factors have been identified. The placenta has been implicated as a potential contributor to neonatal stroke; however, pathology has not been previously described. This case series systematically evaluates prenatal, maternal, and neonatal risk factors and describes placental pathology in 12 cases of neonatal stroke. PATIENTS AND METHODS: We reviewed the Canadian Pediatric Ischemic Stroke Registry from 1992 to 2006, which consists of 186 neonatal stroke patients. Twelve patients with symptomatic cerebral arterial ischemic stroke or sinovenous thrombosis had their placenta available for pathologic examination. Clinical presentation; maternal, prenatal, and neonatal risk factors for stroke; and patient outcome were collected retrospectively from patient charts. Gross and microscopic placental pathology was described and classified into 4 pathologic categories. RESULTS: Of 12 patients studied, 10 patients were male, 5 patients had arterial ischemic stroke, and 7 patients had sinovenous thrombosis. Maternal risk factors were identified in 5 cases, prenatal risk factors in 10 cases, and neonatal risk factors in 10 cases. Placental lesions were present in 10 cases and were classified as thromboinflammatory process in 6 cases, sudden catastrophic event in 5 cases, decreased placental reserve in 3 cases, and stressful intrauterine environment in 2 cases. CONCLUSIONS: This study reviews detailed placental pathology in a selected cohort of patients presenting near the time of delivery and correlates this with clinical presentation, outcome, and risk factors for neonatal stroke. Our results suggest that multiple risk factors are involved in neonatal stroke, and placental pathology may be a contributing factor. The implications of specific placental lesions remain to be determined with larger, case-controlled studies.

Brain biopsy in children with primary small-vessel central nervous system vasculitis.

OBJECTIVE: Primary angiitis of the central nervous system in childhood (cPACNS) is an immune-mediated inflammatory process directed toward blood vessels in the central nervous system. It has been associated with variable clinical and radiological presentations, and devastating consequences without treatment. Brain biopsy is required for definitive diagnosis. The objective of this study was to characterize the clinical and histopathological features of brain biopsies in small-vessel cPACNS (SVcPACNS). METHODS: A single-center prospective cohort study of children diagnosed with cPACNS from 1998 to 2008 was performed. All patients with negative cerebral angiography and brain biopsy were included. Patient data were reviewed for clinical, laboratory, and radiological characteristics at presentation. Standardized brain biopsy review protocols were established, with independent analysis by 2 neuropathologists. Histopathology was correlated with collected clinical data. RESULTS: A total of 13 SVcPACNS patients were included. Ages ranged from 5 to 17 years. Presenting features included seizures (85%), headache (62%), and cognitive decline (54%). Brain biopsy confirmed SVcPACNS in 11 patients with intramural lymphocytic infiltrate. Two had nonspecific perivascular inflammation only. All 6 nonlesional biopsies yielded a diagnosis of SVcPACNS. Lack of specific histological features correlated with prolonged time to biopsy, prior steroid treatment, and inadequate specimen sampling. INTERPRETATION: In children presenting with new onset severe headaches, seizures, or cognitive decline, SVcPACNS and brain biopsy should be considered. Lesional biopsies are preferred; however, nonlesional biopsies may succeed in yielding the diagnosis. Steroid treatment prior to biopsy and inadequate biopsy sampling may obscure the diagnosis in true cases of SVcPACNS.

Treatment of small vessel primary CNS vasculitis in children: an open-label cohort study.

BACKGROUND: There is no treatment protocol or standardised documentation of neurological outcome for patients with small vessel childhood primary angiitis of the CNS, a rare inflammatory brain disease. We aimed to assess a treatment regimen and describe long-term neurological outcomes in a cohort of children with this disorder. METHODS: We did a single-centre open-label cohort study in children with small vessel childhood primary angiitis of the CNS who were less than 18 years old at diagnosis. The treatment protocol consisted of induction therapy with steroids and pulses of intravenous cyclophosphamide followed by maintenance therapy with either azathioprine or mycophenolate mofetil. Clinical and neurological assessments, quality of life measures, and laboratory markers were done at baseline, 3, 6, 9, 12, 18, and 24 months, and every year thereafter. Brain imaging was done at baseline, 6, 12, 18, and 24 months. The primary outcome was the paediatric stroke outcome measure (PSOM) score at 24 months. FINDINGS: From January, 2002, to December, 2009, 127 patients were enrolled, 19 of whom met the inclusion criteria and were given induction therapy. Median age at diagnosis was 9·8 years (range 5·5-17·8) and median follow-up was 33 months (range 1-86). 14 patients completed induction and received maintenance therapy with azathioprine (n=9) or mycophenolate mofetil (n=5). 13 patients completed 24 months' follow-up, nine of whom had a good neurological outcome by PSOM. Eight of 19 patients experienced disease flares. Four patients achieved remission of disease off medication. INTERPRETATION: This treatment protocol of immunosuppressive therapy may improve long-term neurological outcome in children with small vessel childhood primary angiitis of the CNS. Identification and appropriate diagnosis of children with the disorder is crucial because with standardised treatment good neurological outcome is a realistic goal. FUNDING: None.