Mark T Mackay

Murdoch Childrens Research Institute, Melbourne, Victoria, Australia

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Publications (49)177.3 Total impact

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    ABSTRACT: Limited information is available regarding predictors of psychosocial difficulties in children following stroke. This study aimed to (i) compare social competence of children with arterial ischemic stroke (AIS) to those with chronic illness and healthy controls and (ii) investigate the contribution of stroke pathology, neurological outcome and environment. Thirty-six children with AIS > 12 months prior to recruitment were compared with children with chronic illness (asthma) (n = 15) and healthy controls (n = 43). Children underwent intellectual assessment, and children and parents completed questionnaires to assess social competence. Children with AIS underwent MRI scan and neurological evaluation. Child AIS was associated with poorer social adjustment and participation, and children with AIS were rated as having more social problems than controls. Lesion volume was not associated with social outcome, but subcortical stroke was linked to reduced social participation and younger stroke onset predicted better social interaction and higher self-esteem. Family function was the sole predictor of social adjustment. Findings highlight the risk of social impairment following pediatric stroke, with both stroke and environmental factors influencing children's social competence in the chronic stages of recovery. They indicate the potential for intervention targeting support at the family level.
    Social neuroscience. 10/2014; 9(5):471-83.
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    International Journal of Stroke 08/2014; 9(6). · 4.03 Impact Factor
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    ABSTRACT: To determine symptoms, signs, and etiology of brain attacks in children presenting to the emergency department (ED) as a first step for developing a pediatric brain attack pathway. Prospective observational study of children aged 1 month to 18 years with brain attacks (defined as apparently abrupt-onset focal brain dysfunction) and ongoing symptoms or signs on arrival to the ED. Exclusion criteria included epilepsy, hydrocephalus, head trauma, and isolated headache. Etiology was determined after review of clinical data, neuroimaging, and other investigations. A random-effects meta-analysis of similar adult studies was compared with the current study. There were 287 children (46% male) with 301 presentations over 17 months. Thirty-five percent arrived by ambulance. Median symptom duration before arrival was 6 hours (interquartile range 2-28 hours). Median time from triage to medical assessment was 22 minutes (interquartile range 6-55 minutes). Common symptoms included headache (56%), vomiting (36%), focal weakness (35%), numbness (24%), visual disturbance (23%), seizures (21%), and altered consciousness (21%). Common signs included focal weakness (31%), numbness (13%), ataxia (10%), or speech disturbance (8%). Neuroimaging included CT imaging (30%), which was abnormal in 27%, and MRI (31%), which was abnormal in 62%. The most common diagnoses included migraine (28%), seizures (15%), Bell palsy (10%), stroke (7%), and conversion disorders (6%). Relative proportions of conditions in children significantly differed from adults for stroke, migraine, seizures, and conversion disorders. Brain attack etiologies differ from adults, with stroke being the fourth most common diagnosis. These findings will inform development of ED clinical pathways for pediatric brain attacks.
    Neurology 03/2014; · 8.30 Impact Factor
  • Journal of Paediatrics and Child Health 03/2014; 50(3):245-6. · 1.25 Impact Factor
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    ABSTRACT: Background Cardiac disease is a leading cause of stroke in children, yet limited data support the current stroke prevention and treatment recommendations. A multi-disciplinary panel of clinicians was convened in February 2014 by the International Pediatric Stroke Study group to identify knowledge gaps and prioritize clinical research efforts for children with cardiac disease and stroke. Results Significant knowledge gaps exist including a lack of data on stroke incidence, predictors, primary and secondary stroke prevention, hyperacute treatment and outcome in children with cardiac disease. Commonly used diagnostic techniques including brain CT and ultrasound have low rates of stroke detection and diagnosis is frequently delayed. The challenges of research studies in this population include epidemiological barriers to research such as small patient numbers, heterogeneity of cardiac disease, and co-existence of multiple risk factors. Based on stroke burden and study feasibility, studies involving mechanical circulatory support, single ventricle patients, early stroke detection strategies, and understanding secondary stroke risk factors and prevention are the highest research priorities over the next 5 to 10 years. The development of large-scale multi-center and multi-specialty collaborative research is a critical next step. The designation of centers of expertise will assist in clinical care and research. Conclusions There is an urgent need for additional research to improve the quality of evidence in guideline recommendations for cardiogenic stroke in children. While significant barriers to clinical research exist, multi-center and multi-specialty collaboration is an important step towards advancing clinical care and research for children with cardiac disease and stroke.
    Pediatric Neurology. 01/2014;
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    ABSTRACT: Background Social functioning encompasses a range of important skills that an individual uses to interact with the social world. Previous studies suggest that social functioning (outcomes) may be impaired after childhood stroke, but research is limited. AimsWe examined the following: (1) the effect of ischemic stroke upon social outcomes in children; (2) the correlation of cognitive abilities and problem behaviors with social outcomes; and (3) the role of infarct characteristics as predictors of social outcomes. Methods We conducted an observational case-controlled study to compare children with neonatal or childhood onset stroke and controls with chronic asthma. Neurological deficits were measured with the Pediatric Stroke Outcome Measure. Cognitive abilities, problem behavior, adaptive behavior, and social outcomes were assessed with standardized measures. ResultsOverall stroke cases were impaired in several areas of adaptive behaviors but not in cognitive ability, problem behaviors, or social outcomes. Children with more severe neurological deficits had impairments in a range of adaptive behaviors, social adjustment, and social participation. Impaired cognitive ability and more problem behaviors correlated with impaired social adjustment, particularly in stroke cases. Larger infarcts correlated with greater neurological impairment, lower IQ, and poorer social participation. Conclusions Stroke can result in impaired adaptive and social functioning without apparent deficits in IQ or behavior. Infarct size, residual neurological deficits, impaired cognitive ability, and problem behaviors increase the risk for poor social adjustment and participation. These findings can help the clinician anticipate impaired social functioning after pediatric stroke, which is important because age-specific treatments are available.
    International Journal of Stroke 12/2013; · 4.03 Impact Factor
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    ABSTRACT: Background Social functioning encompasses a range of important skills that an individual uses to interact with the social world. Previous studies suggest that social functioning (outcomes) may be impaired after childhood stroke, but research is limited. Aims We examined the following: (1) the effect of ischemic stroke upon social outcomes in children; (2) the correlation of cognitive abilities and problem behaviors with social outcomes; and (3) the role of infarct characteristics as predictors of social outcomes. Methods We conducted an observational case-controlled study to compare children with neonatal or childhood onset stroke and controls with chronic asthma. Neurological deficits were measured with the Pediatric Stroke Outcome Measure. Cognitive abilities, problem behavior, adaptive behavior, and social outcomes were assessed with standardized measures. Results Overall stroke cases were impaired in several areas of adaptive behaviors but not in cognitive ability, problem behaviors, or social outcomes. Children with more severe neurological deficits had impairments in a range of adaptive behaviors, social adjustment, and social participation. Impaired cognitive ability and more problem behaviors correlated with impaired social adjustment, particularly in stroke cases. Larger infarcts correlated with greater neurological impairment, lower IQ, and poorer social participation. Conclusions Stroke can result in impaired adaptive and social functioning without apparent deficits in IQ or behavior. Infarct size, residual neurological deficits, impaired cognitive ability, and problem behaviors increase the risk for poor social adjustment and participation. These findings can help the clinician anticipate impaired social functioning after pediatric stroke, which is important because age-specific treatments are available.
    International Journal of Stroke 12/2013; · 4.03 Impact Factor
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    ABSTRACT: Ketogenic diet is a structured effective treatment for children with intractable epilepsy. Several reports have indicated poor linear growth in children on the diet but the mechanism of poor growth has not been elucidated. We aimed to explore whether the protein to energy ratio plays a role in linear growth of children on ketogenic diet. Data regarding growth and nutrition were, retrospectively, collected from the clinical histories of 35 children who were treated with ketogenic diet for at least 6 months between 2002 and 2010. Patients were stratified into groups according to periods of satisfactory or poor linear growth. Poor linear growth was associated with protein or caloric intake of <80% recommended daily intake, and with a protein-to-energy ratio consistently ≤1.4 g protein/100 kcal even when protein and caloric intakes were adequate. We recommend a protein-to-energy ratio of 1.5 g protein/100 kcal be prescribed to prevent growth retardation.
    Journal of child neurology 12/2013; · 1.59 Impact Factor
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    ABSTRACT: The ability to anticipate deficits would help with implementation of interventions for children affected by stroke. The Pediatric Stroke Outcome Measure (Measure) measures neurological impairment after stroke, but there has been little research examining the relationship between the Measure and functional outcomes. We hypothesized the Measure correlates with cognitive and behavioral outcomes. Thirty-six children with stroke were assessed with the Measure, and tested for cognitive ability, problem behavior, adaptive behavior, and social participation. We examined the correlation between the total Measure and outcomes and determined how subscale scores associated with outcomes. Higher total Measure scores correlated with poorer outcomes in cognitive ability, problem behaviors, adaptive behaviors, and social participation. Specific subscale scores correlated with poorer outcomes in multiple domains. The total Measure can be used to anticipate poor outcomes in multiple domains after stroke and can help the clinician in the treatment of children as they recover.
    Journal of child neurology 10/2013; · 1.59 Impact Factor
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    ABSTRACT: Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS(+) ) in multiplex families and accounts for 70-80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS(+) families could be explained by highly penetrant SCN9A mutations.
    Epilepsia 07/2013; · 3.96 Impact Factor
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    ABSTRACT: This study sought to investigate cognitive outcomes following pediatric arterial ischemic stroke and explore predictors. Participants included 36 children with perinatal or childhood arterial ischemic stroke and a comparison group of 15 children with asthma. Outcomes included cognitive ability, executive functions, and neurological function (Pediatric Stroke Outcome Measure). Magnetic resonance imaging measured lesion location and volume. Mean cognitive scores were at the low end of the average range. Children with arterial ischemic stroke performed significantly below normative populations and significantly below the asthma group on inhibitory control (Cohen's d = .68). Both the Pediatric Stroke Outcome Measure and lesion volume were negatively correlated with cognitive outcome (Spearman r = -.01 to -.42 Pediatric Stroke Outcome Measure; r =-.14 to -.32 Volume). Following arterial ischemic stroke, children performed at the low end of the average range on measures of cognitive functioning. Cognitive outcomes depend on a variety of factors.
    Journal of child neurology 06/2013; · 1.59 Impact Factor
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    ABSTRACT: AIM: Despite advances in medical investigation, many children with neurological conditions remain without a diagnosis, although a genetic aetiology is often suspected. Chromosomal microarray (CMA) screens for copy number variants (CNVs) and long continuous stretches of homozygosity (LCSH) and may further enhance diagnostic yield. Although recent studies have identified pathogenic CNVs in intellectual disability, autism and epilepsy, the utility of CMA testing in a broader cohort of children with neurologic disorders has not been reported. METHODS: Two hundred fifteen patients with neurological conditions of unknown aetiology were seen over a 6-month period and were prospectively tested by CMA using high-resolution single nucleotide polymorphism (SNP) microarrays (Illumina HumanCytoSNP-12 v2.1 or Affymetrix 2.7M). RESULTS: Thirty of 215 (14%) patients tested had an abnormal CMA. Twenty-nine had CNVs (13%) and one (0.5%) a clinically significant stretch of homozygosity. Twenty (9.3%) had a CMA finding considered to be pathogenic or involved in susceptibility to the condition of interest, and 10 (4.7%) had findings of unknown significance. Their phenotypes included infantile spasms and other epilepsies, neuromuscular conditions, ataxia, movement disorders, microcephaly and malformations of cortical development. At least one third of patients did not meet national funding criteria for CMA at the time of presentation. CONCLUSIONS: CMA detected clinically significant abnormalities in a broad range of neurologic phenotypes of unknown aetiology. This test should be considered a first-tier investigation of children with neurologic disorders in whom the initial clinical assessment does not indicate a likely aetiology, especially those with severe epilepsies and neurologically abnormal neonates.
    Journal of Paediatrics and Child Health 06/2013; · 1.25 Impact Factor
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    ABSTRACT: Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.
    Nature Genetics 05/2013; · 35.21 Impact Factor
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    ABSTRACT: OBJECTIVE: To determine the prevalence of hypertension (HPT) in the acute phase after ischemic stroke (IS) and explore its relationship to outcome. METHODS: We performed a retrospective review of children aged 1 month to 18 years with first IS admitted to a tertiary hospital between 2003 and 2008. Blood pressure readings recorded over the first 72 hours after diagnosis and morbidity or mortality at 12 months were documented. HPT was defined as 2 consecutive readings of systolic blood pressure ≥95th percentile for age. RESULTS: Ninety children were identified (median age 3.8 years). Fifty-three of 84 patients (63%) who had blood pressure readings available had at least 1 episode of HPT and 19 (22%) had HPT on 3 consecutive days. HPT was more prevalent at both ends of the age spectrum. The relative risk of 12-month mortality was 4.5 times higher (95% confidence interval = 0.6-34.5, p = 0.096) and relative risk of death in the hospital was 1.7 times higher (95% confidence interval = 1.4-2.0, p = 0.05) if the patient experienced HPT. There was no association between HPT and vascular territory, etiology, or neurologic disability. CONCLUSIONS: HPT is prevalent in children with IS in the first 3 days after diagnosis and is associated with increased risk of death. Larger prospective studies involving systematic recording of blood pressure are required to delineate the impact of HPT on risk of death or disability.
    Neurology 03/2013; · 8.30 Impact Factor
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    ABSTRACT: Aim:  To audit clinical practice and assess early outcomes for infants with epileptic spasms after an agreed initial treatment protocol was adopted. Methods:  We reviewed all cases of epileptic spasms diagnosed between July 2007 and June 2009 and assessed adherence to protocol, remission by day 14, spasm recurrence and side effects. The protocol required that infants be treated with high-dose oral prednisolone except those with tuberous sclerosis complex (TSC) who were treated with vigabatrin. Results:  Twenty-eight infants (age 3-14 months, 17 male) were newly diagnosed. Six (21%) had no cause identified (cryptogenic), six (21%) had TSC and 16 (57%) had other non-TSC symptomatic aetiologies. Twenty-three were treated per protocol and five were not. The proportion with remission by day 14 of treatment was 100% in the cryptogenic group (all treated per protocol), 64% in those with non-TSC symptomatic aetiologies treated per protocol, 20% in those with non-TSC symptomatic aetiologies treated not per protocol and 17% in infants with TSC (all treated per protocol). Of 17 infants who received prednisolone, two were admitted for management of febrile illness. Conclusion:  Our experience with high-dose oral prednisolone for treatment of epileptic spasms suggests that it is effective and tolerable. The greater proportion of non-TSC symptomatic patients with timely cessation of spasms when treated by this protocol supports the use of high-dose oral prednisolone as the treatment of choice. Given the poor response of children with TSC to treatment with vigabatrin, early use of steroid therapy deserves consideration.
    Journal of Paediatrics and Child Health 10/2012; · 1.25 Impact Factor
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    ABSTRACT: Few reports address the role of decompressive craniectomy in children with space-occupying cerebral edema attributable to severe ischemic infarction of the posterior cerebral arterial circulation. We describe four children with posterior circulation arterial ischemic stroke who required decompressive craniectomy. These children accounted for 11% of all cases of posterior circulation ischemic stroke at our institution from 2002-2010. Three manifested large, cerebellar hemispheric infarcts, and one manifested a large, temporo-occipital posterior cerebral artery infarct. Deterioration occurred within 72 hours of stroke onset. Two patients demonstrated minimal functional deficits at follow-up, and two demonstrated moderate deficits with functional limitations. Because decompressive craniectomy can be lifesaving in children with severe posterior circulation arterial ischemic stroke, early neurosurgical referral should be considered.
    Pediatric Neurology 09/2012; 47(3):193-7. · 1.42 Impact Factor
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    ABSTRACT: Human herpesvirus 6 (HHV6) is the major cause of posttransplant acute limbic encephalitis (PALE) in immunosuppressed patients following hematopoietic stem cell transplant. Memory impairment and temporal lobe epilepsy following PALE are reported in adults, but sequelae in young children are unknown. We report three children with HHV6-associated PALE 20-23 days after cord blood transplantation for leukemias who developed symptomatic generalized epilepsy. Patients were followed for 2-8 years and underwent magnetic resonance imaging (MRI) and video-electroencephalography (EEG). Two patients underwent viral and autoimmune testing and immunotherapies. Generalized seizures, including tonic seizures, developed 11-18 months after HHV6-associated PALE. Seizures were frequent and resistant to multiple antiepileptic drugs (AEDs). Generalized slow spike-wave and low-voltage fast activity were recorded on interictal and ictal EEGs. The two younger patients regressed in their general abilities, synchronous with seizure evolution, whereas the older patient developed a severe amnestic syndrome that halted intellectual development. Serial MRI studies revealed bilateral signal change and atrophy in the medial temporal structures of all patients. In the two investigated patients, there was no evidence of chronic HHV6 infection, minimal evidence of cerebral inflammation, and no significant improvement with pulse with intravenous methylprednisolone and immunoglobulin. The severe and generalized seizure, cognitive, and EEG sequelae of HHV6-related PALE in these children may be due to a chronic, viral, or immune-mediated inflammatory process or developmental epileptogenesis resulting from bilateral hippocampal injury at an early age, although there was a paucity of evidence for either.
    Epilepsia 05/2012; 53(7):e122-6. · 3.96 Impact Factor
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    ABSTRACT: We report the efficacy of the ketogenic diet in refractory epilepsies focusing on outcomes with regard to epilepsy syndromes and etiology in children and adults with refractory epilepsy. Sixty-four consecutive children and four adults were prospectively enrolled from 2002 to 2009; seven were excluded from analysis. The classical ketogenic diet was initiated on an inpatient basis with dietary ratios ranging from 2:1 to 4:1 fat to carbohydrate and protein. Patients were classified according to syndrome and etiology using the 1989 and more recent 2010 International League Against Epilepsy (ILAE) classification systems. Responders were defined as >50% reduction in seizure frequency compared to baseline. Syndromes included symptomatic generalized (52), genetic (idiopathic) generalized (7), and focal epilepsies (2) and etiologies included structural (24), genetic (18), and unknown (19). Twenty-nine (48%) of 61 patients were responders at 3 months. Two children became seizure-free: one with focal epilepsy of unknown etiology and another with refractory childhood absence epilepsy. Responsive syndromes included migrating partial epilepsy of infancy, childhood absence epilepsy, focal epilepsy, epilepsy with myoclonic-atonic seizures, and Dravet syndrome. Children with lissencephaly and hypoxic ischemic encephalopathy had surprisingly good responses. The ketogenic diet is an effective treatment for children and adults with refractory epilepsy. The response is predicted by type of epilepsy syndrome. Accurate characterization of the electroclinical syndrome is an important factor in decisions about timing of initiation of the ketogenic diet.
    Epilepsia 03/2012; 53(3):e55-9. · 3.96 Impact Factor
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    ABSTRACT: Febrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children and evolves into a chronic, refractory, focal epilepsy with associated cognitive and behavioral difficulties. Herein we describe the features of the chronic epilepsy and critically review evidence for the etiology of this syndrome. Seven patients with FIRES were studied. The duration of follow-up in six survivors was 5-17 years. Clinical, electroencephalography (EEG), neuroimaging, and other investigative findings during the acute and chronic phases were reviewed. These previously normal children presented with a febrile illness and status epilepticus that was refractory to antiepileptic medications in all children, to immunotherapies (including immunoglobulin, corticosteroids, plasma exchange, and rituximab) in four, and to acute vagus nerve stimulation in one. Markers of cerebral inflammation were few and response to antiepileptic and immunomodulatory therapies was poor. Evolution to chronic epilepsy occurred without a silent period. Seizure characteristics in the chronic phase were strikingly stereotyped and similar to the acute phase, with head and eye version, unilateral facial jerking, asymmetric tonic posturing, and unilateral limb jerking in all patients. Electrographic ictal onset was lateralized in all recorded seizures, unilateral in one patient, and independent bilateral in three. Seizures were refractory to multiple antiepileptic medications in all patients and partly responsive to chronic vagus nerve stimulation in two patients. Moderate to severe intellectual impairment was noted in four patients, and borderline intellectual abilities were noted in two. Magnetic resonance imaging (MRI) in the chronic phase was normal in three patients and showed mild diffuse cortical atrophy and/or mild hippocampal atrophy or sclerosis in three. The similar perirolandic and perisylvian features of acute and chronic seizures, the lack of a silent period, the absence of evidence of cerebral inflammation, and the poor response to immunotherapies suggest FIRES is best conceptualized as a chronic epilepsy with explosive onset, not a remote-symptomatic epilepsy with an acute inflammatory antecedent.
    Epilepsia 12/2011; 53(1):101-10. · 3.96 Impact Factor
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    ABSTRACT: The implementation of uniform nomenclature and classification in adult arterial ischemic stroke (AIS) has been critical for defining outcomes and recurrence risks according to etiology and in developing risk-stratified treatments. In contrast, current classification and nomenclature in childhood AIS are often overlapping or contradictory. Our purpose was to develop a comprehensive consensus-based classification system for childhood AIS. Using a modified-Delphi method, members of the International Pediatric Stroke Study (IPSS) developed the Childhood AIS Standardized Classification And Diagnostic Evaluation (CASCADE) criteria. Two groups of pediatric stroke specialists from the IPSS classified 7 test cases using 2 methods each: (1) classification typical of the individual clinician's current clinical practice; and (2) classification based on the CASCADE criteria. Group 1 underwent in-person training in the utilization of the CASCADE criteria. Group 2 classified the same cases via an online survey, including definitions but without training. Inter-rater reliability (IRR) was assessed via multi-rater unweighted κ-statistic. In Group 1 (with training), IRR was improved using CASCADE criteria (κ=0.78, 95% CI=[0.49, 0.94]), compared with typical clinical practice (κ=0.40, 95% CI=[0.11, 0.60]). In Group 2 (without training), IRR was lower than among trained raters (κ=0.61, 95% CI=[0.29, 0.77]), but higher than current practice (κ=0.23, 95% CI=[0.03, 0.36]). A new, consensus-based classification system for childhood AIS, the CASCADE criteria, can be used to classify cases with good IRR. These preliminary findings suggest that the CASCADE criteria may be particularity useful in the setting of prospective multicenter studies in childhood-onset AIS, where standardized training of investigators is feasible.
    Stroke 12/2011; 43(2):371-7. · 6.16 Impact Factor

Publication Stats

384 Citations
177.30 Total Impact Points

Institutions

  • 2008–2013
    • Murdoch Childrens Research Institute
      Melbourne, Victoria, Australia
  • 2006–2012
    • The Royal Children's Hospital
      • • Children's Neuroscience Centre (CNC)
      • • Paediatric Rehabilitation Service
      Melbourne, Victoria, Australia
  • 2008–2011
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 2005–2011
    • University of Melbourne
      • • Department of Paediatrics
      • • Department of Medicine
      Melbourne, Victoria, Australia
  • 2009
    • Box Hill Institute
      Melbourne, Victoria, Australia