Paola Pergami

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.

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.

Inflammatory Biomarkers in Childhood Arterial Ischemic Stroke: Correlates of Stroke Cause and Recurrence.

Background and Purpose— Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS. Methods— In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-&agr;. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS. Results— Median age at index stroke was 8.2 years (interquartile range, 3.6–14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3–10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies. Conclusions— Among children with AIS, specific inflammatory biomarkers correlate with cause and—in the arteriopathy group—risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.Among children with arterial ischemic stroke (AIS), those with arteriopathy have the highest recurrence risk. We hypothesized that arteriopathy progression is an inflammatory process and that inflammatory biomarkers would predict recurrent AIS.In an international study of childhood AIS, we selected cases classified into 1 of the 3 most common childhood AIS causes: definite arteriopathic (n=103), cardioembolic (n=55), or idiopathic (n=78). We measured serum concentrations of high-sensitivity C-reactive protein, serum amyloid A, myeloperoxidase, and tumor necrosis factor-α. We used linear regression to compare analyte concentrations across the subtypes and Cox proportional hazards models to determine predictors of recurrent AIS.Median age at index stroke was 8.2 years (interquartile range, 3.6-14.3); serum samples were collected at median 5.5 days post stroke (interquartile range, 3-10 days). In adjusted models (including age, infarct volume, and time to sample collection) with idiopathic as the reference, the cardioembolic (but not arteriopathic) group had higher concentrations of high-sensitivity C-reactive protein and myeloperoxidase, whereas both cardioembolic and arteriopathic groups had higher serum amyloid A. In the arteriopathic (but not cardioembolic) group, higher high-sensitivity C-reactive protein and serum amyloid A predicted recurrent AIS. Children with progressive arteriopathies on follow-up imaging had higher recurrence rates, and a trend toward higher high-sensitivity C-reactive protein and serum amyloid A, compared with children with stable or improved arteriopathies.Among children with AIS, specific inflammatory biomarkers correlate with cause and-in the arteriopathy group-risk of stroke recurrence. Interventions targeting inflammation should be considered for pediatric secondary stroke prevention trials.

Motor demand-dependent improvement in accuracy following low-frequency transcranial magnetic stimulation of left motor cortex.

The role of primary motor cortex (M1) in the control of voluntary movements is still unclear. In brain functional imaging studies of unilateral hand performance, bilateral M1 activation is inconsistently observed, and disruptions of M1 using repetitive transcranial magnetic stimulation (rTMS) lead to variable results in the hand motor performance. As the motor tasks differed qualitatively in these studies, it is conceivable that M1 contribution differs depending on the level of skillfulness. The objective of the present study was to determine whether M1 contribution to hand motor performance differed depending on the level of precision of the motor task. Here, we used low-frequency rTMS of left M1 to determine its effect on the performance of a pointing task that allows the parametric increase of the level of precision and thereby increase the level of required precision quantitatively. We found that low-frequency rTMS improved performance in both hands for the task with the highest demand on precision, whereas performance remained unchanged for the tasks with lower demands. These results suggest that the functional relevance of M1 activity for motor performance changes as a function of motor demand. The bilateral effect of rTMS to left M1 would also support the notion of M1 functions at a higher level in motor control by integrating afferent input from nonprimary motor areas.

Prolonged or recurrent acute seizures after pediatric arterial ischemic stroke are associated with increasing epilepsy risk

To determine epilepsy risk factors after pediatric stroke.

Conditions for enhancing the encoding of an elementary motor memory by rTMS.

OBJECTIVE Motor learning results in changes of movement representation in primary motor cortex (M1) a process involving long-term potentiation (LTP). Pairing motor training with repetitive transcranial magnetic stimulation (rTMS) of M1 enhances the formation of a motor memory. Here we determined the effect of pairing M1 stimulation and the execution of training movements at different times and frequencies on the formation of a motor memory. METHODS Formation of a motor memory was defined as increases in motor evoked potentials (MEP) of the training agonist (extensor carpi ulnaris muscle, ECU) and increases in peak acceleration of the trained movements that last more than 60min. Training consisted of auditory-paced ballistic wrist extension movements (30min, 0.5Hz) paired with 0.1, 0.25 or 0.5Hz subthreshold rTMS. The rTMS pulse was applied at either the onset, 100ms prior to or 300ms after the onset of training movement related increases in electromyographic (EMG) activity of ECU. This was compared to a Sham condition. RESULTS Only 0.1Hz rTMS applied at the onset of the training related increase in ECU-EMG activity resulted in increases in MEP amplitudes and peak acceleration when compared to the Sham. CONCLUSIONS The formation of motor memory is enhanced above the naïve level by co-administration of low frequency rTMS at the time of execution of training movements. SIGNIFICANCE These results indicate the importance of time and frequency of rTMS in these settings and should be considered in the design of rehabilitation treatment strategies using rTMS.

Gait parameters associated with balance in healthy 2- to 4-year-old children

The use of validated measurements of gait and balance are crucial to establish baseline function and assess effectiveness of therapeutic interventions. Gait in children changes with motor development requiring frequent observations to effectively track progress. Standardized baseline spatiotemporal measurements and a greater understanding of the relationship between gait and balance would provide important feedback to clinicians regarding the effectiveness of rehabilitation and guide treatment modifications. 84 subjects (2.0-4.9 years) walked along the GAITRite(®), a walkway that records spatiotemporal parameters. The Pediatric Balance Scale (PBS) was administered to assess balance. Comparison of spatiotemporal parameter means between age groups showed trends associated with motor development similar to the ones described in the literature such as decreased cadence and increased step/stride length with increasing age. However, no significant differences in normalized spatiotemporal parameters were found between age groups. Age, leg length, cadence, step/stride length, step/stance time, and single/double support time showed significant correlation with balance scores. When the parameters were grouped into spatial, temporal, and age-related components using principal components analysis and included in a multiple regression model, they significantly predicted 51% of the balance score variance. Age-related components most strongly predicted balance outcomes. We suggest that balance can potentially be evaluated by assessment of spatial, temporal, and age-related characteristics of gait such as step length, cadence, and leg length. This suggests the possibility of developing new gait measurement technology that could provide functional assessment and track improvements during rehabilitation regimens. If the same model can be applied to monitor treatment efficacy in children with gait abnormalities remains to be addressed.

Effects of monoaminergic drugs on training-induced motor cortex plasticity in older adults

Primary motor cortex (M1) plasticity is involved in motor learning and stroke motor recovery, and enhanced by increasing monoaminergic transmission. Age impacts these processes but there is a paucity of systematic studies on the effects of monoaminergic drugs in older adults. Here, in ten older adults (age 61+4years, 4 males), we determine the effects of a single oral dose of carbidopa/levodopa (DOPA), d-amphetamine (AMPH), methylphenidate (MEPH) and placebo (PLAC) on M1 excitability and motor training-induced M1 plasticity. M1 plasticity is defined as training related long lasting changes in M1 excitability and kinematics of the trained movement. At peak plasma level of the drugs, subjects trained wrist extension movements for 30min. Outcome measures were motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation at increasing intensity (stimulus response curve, SRC) and peak acceleration of the trained wrist extension movements. Measures were obtained before and after completion of training. The curve parameters plateau (MEPmax), inflection point, and slope were extracted from SRC. At baseline drugs had a differential effect on curve parameters, while kinematics remained unchanged. Training alone (PLAC) increased MEPmax but did not improve kinematics. Drugs affected training-related changes of the curve parameters differently, but did not enhance them or kinematics when compared to PLAC. The results demonstrate that in the older adults, MEPH, DOPA, or AMPH have differential effects on baseline M1 excitability and training-related M1 plasticity but fail to enhance them above the naïve level.

Nocturnal headaches and pulsatile cranial mass: the tip of an iceberg.

BACKGROUND Capillary malformation-arteriovenous malformation (CM-AVM) disorder is a newly defined hereditary disorder of the vasculature with typical defining features that include cutaneous capillary malformations associated with high-flow lesions in various other organ systems. Mutations on the RASA1 gene are reported to be associated with a variety of vascular malformations and present with a widely varying phenotype. PATIENT A healthy 3 year old presented with acute onset of severe nocturnal headaches, nausea, and vomiting associated with a 2-cm pulsatile mass and prominent superficial veins on her forehead. Neuroimaging demonstrated a complex vascular malformation with multiple arteriovenous fistulae and cavernous angiomas present in multiple locations in the brain, but not in any other organ system. RESULTS The patient was found to have a mutation of the RASA1 gene, which has not been previously described in the literature. CONCLUSIONS This case describes a new RASA1 mutation with a phenotype that has not been previously described with a combination of pial fistulae and intracranial AV fistula in the absence of arteriovenous malformations.

Impact of anticoagulation on the short-term outcome in a population of neonates with cerebral sinovenous thrombosis: a retrospective study.

To investigate the impact of anticoagulation on short-term outcome (1 month) in neonates with cerebral sinovenous thrombosis, the authors conducted a retrospective chart review of neonates admitted to 2 tertiary hospitals over a 5- and 8-year period, respectively. Neonates with confirmed radiographic evidence of cerebral sinovenous thrombosis were included. Eighteen total patients treated with hydration only were identified. Approximately 50% of these neonates showed clot extension or other complications on follow-up imaging that were obtained within 72 hours with either magnetic resonance imaging or computed topography. Five neonates were treated with anticoagulation, and none of these patients developed new infarcts or hemorrhages. The results of this retrospective study suggest that anticoagulation is safe in neonates with cerebral sinovenous thrombosis. Early follow-up scans can help treatment decision. Larger studies are needed to develop standardized guidelines for the evaluation and treatment of neonatal cerebral sinovenous thrombosis.