Mubeen F. Rafay

Delay to Diagnosis in Acute Pediatric Arterial Ischemic Stroke

Background and Purpose— For the clinician, the diagnosis of arterial ischemic stroke (AIS) in children is a challenge. Prompt diagnosis of pediatric AIS within 6 hours enables stroke-specific thrombolytic and neuroprotective strategies. Methods— We conducted a retrospective study of prospectively enrolled consecutive cohort of children with AIS, admitted to The Hospital for Sick Children, Toronto, from January 1992 to December 2004. The data on clinical presentation, symptom onset, emergency department arrival, neuroimaging and stroke diagnosis were recorded. The putative predictors of delayed diagnosis were selected a priori for analysis. Results— A total of 209 children with AIS were studied. The median interval from symptom onset to AIS diagnosis was 22.7 hours (interquartile range: 7.1 to 57.7 hours), prehospital delay (symptom onset to hospital arrival) was 1.7 hours (interquartile range: 49 minutes to 8.1 hours), and the in-hospital delay (presentation to diagnosis) was 12.7 hours (interquartile range: 4.5 to 33.5 hours). The initial assessment was completed in 16 minutes and initial neuroimaging in 8.8 hours. The diagnosis of AIS was suspected on initial assessment in 79 (38%) children and the initial neuroimaging diagnosed AIS in 47%. The parent’s help seeking action, nonabrupt onset of symptoms, altered consciousness, milder stroke severity, posterior circulation infarction and lack of initial neuroimaging at a tertiary hospital were predictive delayed AIS diagnosis. Conclusion— In the diagnosis of AIS, significant prehospital and in-hospital delays exist in children. Several predictors of the delayed AIS diagnosis were identified in the present study. Efforts to target these predictors can reduce diagnostic delays and optimize the management of AIS in children.

Craniocervical Arterial Dissection in Children: Clinical and Radiographic Presentation and Outcome

Craniocervical arterial dissection is a recognized cause of arterial ischemic stroke in children. Whether children with craniocervical arterial dissection have dissection characteristics different from those of adults is unclear. A retrospective review of children, 1 month to 18 years of age, with dissection from two Canadian pediatric ischemic stroke registry centers was conducted. From 213 patients with arterial ischemic stroke, 16 (7.5%) were identified with dissection, 37.5% had warning symptoms, and 50% had a history of head or neck trauma. The clinical presentation included headache (44%), altered consciousness (25%), seizures (12.5%), and focal deficits (87.5%). Dissection involved extracranial vessels in 75% and anterior circulation in 56%. Follow-up included complete recovery in 43%, mild to moderate deficits in 44%, and severe deficits in 13%. Fourteen (87.5%) children received antithrombotic treatment. Follow-up angiography showed resolution of abnormalities in 60% of vessels. Total occlusion had the worst outcome for recanalization. In conclusion, the etiology of arterial dissection in the majority of children appears to be either trauma or idiopathic. Long-term angiography shows variable outcomes, depending on the initial findings. The relationship of angiographic outcomes with recurrent strokes requires further study in pediatric dissection. ( J Child Neurol 2006;21:8—16).

Antithrombotic treatment in neonatal cerebral sinovenous thrombosis: results of the International Pediatric Stroke Study

OBJECTIVE To identify predictors of antithrombotic treatment in neonates with cerebral sinovenous thrombosis (CSVT) in a large multinational study. STUDY DESIGN Neonates with CSVT from 10 countries were enrolled in the International Pediatric Stroke Study from 2003 through 2007. Term neonates with CSVT who presented with neurologic symptoms or signs of systemic illness and neuroimaging evidence of thrombus or flow interruption within cerebral venous system were included. RESULTS Of 341 neonates enrolled, 84 had isolated CSVT. Neuroimaging findings, available in 67/84 neonates, included venous ischemic infarction in 5, hemorrhagic infarction or other intracranial hemorrhage in 13, both infarction and hemorrhage in 26, and no parenchymal lesions in 23. Treatment data, available in 81/84 neonates, included antithrombotic medications in 52% (n = 43), comprising heparin (n = 14), low molecular weight heparin (n = 34), warfarin (n = 1), and aspirin (n = 2). By univariate logistic regression analysis, deep venous system thrombosis (P = .05) and location in the United States (P = .001) predicted nontreatment. Presence of infarction, hemorrhage, dehydration, systemic illness, and age did not predict treatment or nontreatment. In multivariate analysis only geographic location remained significant. CONCLUSIONS In neonatal CSVT, regional antithrombotic treatment practices demonstrate considerable variability and uncertainty about indications for antithrombotic therapy. Additional studies are warranted.

Canadian stroke best practice recommendations: Stroke rehabilitation practice guidelines, update 2015:

Stroke rehabilitation is a progressive, dynamic, goal-orientated process aimed at enabling a person with impairment to reach their optimal physical, cognitive, emotional, communicative, social and/or functional activity level. After a stroke, patients often continue to require rehabilitation for persistent deficits related to spasticity, upper and lower extremity dysfunction, shoulder and central pain, mobility/gait, dysphagia, vision, and communication. Each year in Canada 62,000 people experience a stroke. Among stroke survivors, over 6500 individuals access in-patient stroke rehabilitation and stay a median of 30 days (inter-quartile range 19 to 45 days). The 2015 update of the Canadian Stroke Best Practice Recommendations: Stroke Rehabilitation Practice Guidelines is a comprehensive summary of current evidence-based recommendations for all members of multidisciplinary teams working in a range of settings, who provide care to patients following stroke. These recommendations have been developed to address both the organization of stroke rehabilitation within a system of care (i.e., Initial Rehabilitation Assessment; Stroke Rehabilitation Units; Stroke Rehabilitation Teams; Delivery; Outpatient and Community-Based Rehabilitation), and specific interventions and management in stroke recovery and direct clinical care (i.e., Upper Extremity Dysfunction; Lower Extremity Dysfunction; Dysphagia and Malnutrition; Visual-Perceptual Deficits; Central Pain; Communication; Life Roles). In addition, stroke happens at any age, and therefore a new section has been added to the 2015 update to highlight components of stroke rehabilitation for children who have experienced a stroke, either prenatally, as a newborn, or during childhood. All recommendations have been assigned a level of evidence which reflects the strength and quality of current research evidence available to support the recommendation. The updated Rehabilitation Clinical Practice Guidelines feature several additions that reflect new research areas and stronger evidence for already existing recommendations. It is anticipated that these guidelines will provide direction and standardization for patients, families/caregiver(s), and clinicians within Canada and internationally.

The Risks and Safety of Clopidogrel in Pediatric Arterial Ischemic Stroke

Background and Purpose— The purpose of this study was to determine safety and tolerability of clopidogrel in children with arterial ischemic stroke (AIS). Clopidogrel is the alternative antiplatelet medication when aspirin is not tolerated or fails. The possible risks and safety of clopidogrel in children with AIS have not been assessed. Methods— This is a prospective consecutive cohort study of children with AIS who were started on clopidogrel. Seventeen children were included. Results— Two children developed subdural hematomas while on clopidogrel in conjunction with aspirin. Two others had headache or hand numbness. No other side effects like rash or gastrointestinal upsets were reported. Conclusions— We found clopidogrel to be relatively well tolerated in the pediatric population. In combination with aspirin and in the presence of other risk factors, intracranial bleeding may be seen.

Arteriopathy Diagnosis in Childhood Arterial Ischemic Stroke Results of the Vascular Effects of Infection in Pediatric Stroke Study

Background and Purpose Although arteriopathies are the most common cause of childhood arterial ischemic stroke (AIS), and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with AIS.Background and Purpose— Although arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke. Methods— Vascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step. Results— Cases were aged median 7.6 years (interquartile range, 2.8–14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (&kgr;=0.77, 0.81, and 0.78). Conclusions— Clinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Mode of Onset Predicts Etiological Diagnosis of Arterial Ischemic Stroke in Children

Background and Purpose— In children, early differentiation among various etiologies of arterial ischemic stroke (AIS) is important. Cerebral arteriopathy is a frequently identified cause of childhood stroke. Children with arteriopathies require a different therapeutic approach from children with AIS of nonarteriopathic origin. We aimed to investigate the association between temporal features of the onset of neurological symptoms and stroke etiology in children with AIS. Methods— From a consecutive cohort of children (6 months to 18 years) with a confirmed diagnosis of AIS at one center, we selected all patients with transient cerebral arteriopathy (n=10), postvaricella angiopathy (n=20), dissection (n=8), cardio-embolic (n=8), and cryptogenic stroke (n=10). We retrospectively reviewed medical charts for mode of onset and classified the onset as either abrupt, reaching maximum severity of symptoms within 30 minutes, or nonabrupt, including a progressing, stuttering, or recurring course. We compared the mode of onset in patients with known cerebral arteriopathy to those with nonarteriopathic stroke using multivariate logistic regression modeling. Results— There were no significant differences for age, gender, location of infarction, seizures, and headache between the arteriopathic and nonarteriopathic group. Most children with nonarteriopathic AIS had an abrupt onset (72%), compared with 32% in children with arteriopathic stroke. With nonabrupt onset, the odds of having an arteriopathic etiology was 6.1 (95% CI, 1.6 to 22.8; P=0.007) after correction for possible confounders. Conclusions— Mode of onset predicts etiological diagnosis of childhood AIS and may guide prioritization of ancillary investigations and choice of treatment. A nonabrupt onset of symptoms is associated with arteriopathic stroke, particularly with presumed inflammatory arteriopathies.

Risk of Recurrent Arterial Ischemic Stroke in Childhood A Prospective International Study

Background and Purpose— Published cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era. Methods— The Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review. Results— Of the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0–3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%–10%) at 1 month and 12% (8.5%–15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8–14). The 1-year recurrence rate was 32% (95% confidence interval, 18%–51%) for moyamoya, 25% (12%–48%) for transient cerebral arteriopathy, and 19% (8.5%–40%) for arterial dissection. Conclusions— Children with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed.

Predictive Value of Clinical and EEG Features in the Diagnosis of Stroke and Hypoxic Ischemic Encephalopathy in Neonates With Seizures

Background and Purpose— In neonates, the differentiation of stroke and hypoxic ischemic encephalopathy (HIE) is important. Neuroimaging presents technical challenges in unstable neonates, resulting in frequently delayed or missed diagnosis of stroke. Differentiating clinical and electroencephalographic (EEG) features would assist physicians in the timely diagnosis. We sought to determine, in neonates with seizures, clinical and EEG features that differentiate stroke and HIE. Methods— Retrospective cohort study comparing clinical, seizure, and EEG features in term neonates with ischemic stroke or HIE and seizures within 7 days after birth, admitted at The Hospital for Sick Children. Putative clinical and EEG predictors of stroke were analyzed with univariate and multivariate methods. Results— Sixty-two newborns with stroke (n=27) or HIE (n=35) were studied. With univariate analysis, predictors of stroke included delayed seizure onset (≥12-hours after birth) (P<0.0001; OR, 26.4; 95% CI, 6.8, 102.5), focal motor seizures (P=0.001; OR, 7.2; 95% CI, 2.0, 26.0) and pattern of neurological abnormalities (P<0.0001). With multivariate analysis, delayed seizure onset (P<0.0001; OR 39.7; 95% CI, 7.3, 217.0) and focal motor seizures (P=0.007; OR, 13.4; 95% CI, 2.1, 87.9) predicted stroke. Presence of both predictors had 100% positive predictive value and specificity, 61% negative predictive value and 37% sensitivity. Conclusions— In neonates, onset of seizures beyond 12 hours of birth and clinically observed focal seizures are predictive of stroke. These preinvestigation indicators of stroke may facilitate earlier diagnosis and institution of specific management strategies.

Pathological Evidence of Vacuolar Myelinopathy in a Child Following Vigabatrin Administration

Vigabatrin, a γ-aminobutyric acid (GABA) aminotransferase— inhibiting drug used for seizure control, has been associated with white matter vacuolation and intramyelinic edema in animal studies. Similar pathological lesions have never been described in the central nervous system of human participants treated with the drug. Described here is a child with quadriparetic cerebral palsy secondary to hypoxic-ischemic brain injury following premature birth, who received vigabatrin for the treatment of infantile spasms at 9 months of age. A severe deterioration of neurologic function immediately followed the initiation of vigabatrin, and the child died 3 weeks later. Neuropathological examination revealed white matter vacuolation and intramyelinic edema. This represents the first reported case of vigabatrin-induced intramyelinic edema in humans. It validates the concerns regarding vigabatrin safety in infants and individuals with preexisting abnormalities of myelin.