Steven G. Pavlakis

Sickle cell disease: The neurological complications

The genetic cause of sickle cell disease has been known for decades, yet the reasons for its clinical variability are not fully understood. The neurological complications result from one point mutation that causes vasculopathy of both large and small vessels. Anemia and the resultant cerebral hyperemia produce conditions of hemodynamic insufficiency. Sickled cells adhere to the endothelium, contributing to a cascade of activated inflammatory cells and clotting factors, which result in a nidus for thrombus formation. Because the cerebrovascular reserve becomes exhausted, the capacity for compensatory cerebral mechanisms is severely limited. There is evidence of small‐vessel sludging, and a relative deficiency of nitric oxide in these vessels further reduces compensatory vasodilatation. Both clinical strokes and silent infarcts occur, affecting motor and cognitive function. New data suggest that, in addition to sickle cell disease, other factors, both environmental (eg, hypoxia and inflammation) and genetic (eg, mutations resulting in thrombogenesis), may contribute to a patients stroke risk. The stroke risk is polygenic, and sickle cell disease can be considered a model for all cerebrovascular disease. This complex disease underscores the potential intellectual and practical distance between the determination of molecular genetics and effective clinical application and therapeutics.

Hemodynamic Etiology of Elevated Flow Velocity and Stroke in Sickle-Cell Disease

Elevation of blood flow velocity in the large cerebral vessels is known to be of substantial pathophysiologic and prognostic significance in sickle-cell disease (SCD). Its precise cause is not established, but the two obvious proximal mechanisms are obstructive vascular stenosis and hemodynamic dilatation. Here we revisit this distinction by analyzing cerebrovascular reserve capacity. Forty-two patients with SCD underwent measurements of global cerebral blood flow in grey matter by the 133Xe inhalation method during normocapnia and hypercapnia to quantify cerebrovascular reactivity. Cerebral blood flow was significantly higher in SCD patients (120±31 ml/100 g/min) than in controls (76±20 ml/100 g/min). Reactivity was significantly lower in SCD patients (1.06±1.92 versus 2.16±1.15%/mm Hg). Stepwise multiple regressions within the SCD sample determined that normocapnic cerebral blood flow was largely predicted by hematocrit (r =–0.59; P > 0.0001), whereas hypercapnic reactivity was only predicted by normocapnic flow across all subjects (r =–0.52; P > 0.0001). None of the controls, but 24% of the SCD patients showed ‘steal’ (negative reactivity, χ2 = 6.05; P > 0.02). This impairment of vasodilatory capacity, occurring at perfusion levels above 150 ml/100 g/min, may reflect intrinsic limitations of the human cerebrovascular system and can explain both the elevated blood flow velocities and the high risk of stroke observed in such patients.

MRI abnormalities of the brain in one-year-old children with sickle cell anemia

Sickle cell anemia (SCA) frequently results in damage to the central nervous system (CNS), but the age of onset of these effects is uncertain. We performed MRI examinations of the brain in infants with SCA, who were evaluated as part of the multicenter randomized double‐blinded Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG).

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.

Sickle cell disease: ischemia and seizures

Although the prevalence of seizures in children with sickle cell disease (SCD) is 10 times that of the general population, there are few prospectively collected data on mechanism. With transcranial Doppler and magnetic resonance imaging (MRI) and angiography, we evaluated 76 patients with sickle cell disease, 29 asymptomatic and 47 with neurological complications (seizures, stroke, transient ischemic attack, learning difficulty, headaches, or abnormal transcranial Doppler), who also underwent bolus‐tracking perfusion MRI. The six patients with recent seizures also had electroencephalography. Group comparisons (seizure, nonseizure, and asymptomatic) indicated that abnormal transcranial Doppler was more common in the seizure (4/6; 67%) and nonseizure (26/41; 63%) groups than in the asymptomatic (10/29; 34%) group (χ2; p = 0.045), but abnormal structural MRI (χ2; p = 0.7) or magnetic resonance angiography (χ2; p = 0.2) were not. Relative decreased cerebral perfusion was found in all seizure patients and in 16 of 32 of the remaining patients with successful perfusion MRI (p = 0.03). In the seizure patients, the perfusion abnormalities in five were ipsilateral to electroencephalographic abnormalities; one had normal electroencephalogram results. These findings suggest that vasculopathy and focal hypoperfusion may be factors in the development of sickle cell disease–associated seizures. Ann Neurol 2005;58:290–302

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.

The effects of hypertension on the paediatric brain: a justifiable concern

The prevalence of hypertension in children is increasing but its neurological effects are under-recognised. Here, we describe acute and chronic effects of childhood hypertension on the nervous system. Acute neurological involvement ranges from posterior reversible encephalopathy syndrome to, possibly, infarction and haemorrhage. Children with chronic hypertension are likely to have learning disabilities and deficiencies in executive function, which are potentially reversible with antihypertensive treatment. These cognitive defects may be secondary to abnormal regulation of cerebral blood flow. Raised blood pressure in childhood could also contribute to the early development of atherosclerosis, which can have both short-term and long-term adverse effects on vasculature. Clinical studies are needed to better define the full clinical range of paediatric hypertension on a childs nervous system. Furthermore, accurate biomarkers to define cognitive abnormalities and cerebral involvement need to be identified.

Hypertension Impairs Vascular Reactivity in the Pediatric Brain

Background and Purpose— Chronic hypertension impairs cerebrovascular regulation in adults, but its effects on the pediatric population are unknown. The objective of this study was to investigate cerebrovascular abnormalities in hypertensive children and adolescents. Methods— Sixty-four children and adolescents aged 7 to 20 years underwent transcranial Doppler examinations of the middle cerebral artery at the time of rebreathing CO2. Time-averaged maximum mean cerebral blood flow velocity and end-tidal CO2 were used to quantify cerebrovascular reactivity during hypercapnia. Patients were clinically categorized as hypertensive, prehypertensive, or white coat hypertensive based on 24-hour ambulatory blood pressure measurements. Their reactivities were compared with 9 normotensive control subjects and evaluated against baseline mean blood pressure z-scores and loads. Results— Untreated hypertensive children had significantly lower hypercapnic reactivity than normotensive children (2.556±1.832 cm/s · mm Hg versus 4.256±1.334 cm/s · mm Hg, P<0.05). Baseline mean diastolic blood pressure z-scores (r=−0.331, P=0.037) and diastolic blood pressure loads (r=−0.351, P=0.026) were inversely related to reactivity. Conclusions— Untreated hypertensive children and adolescents have blunted reactivity to hypercapnia, indicating deranged vasodilatory reactivity. The inverse relationship between diastolic blood pressure indices and reactivity suggests that diastolic blood pressure may be a better predictor of cerebral end organ damage than systolic blood pressure.

Transcranial Doppler Ultrasonography (TCD) in Infants with Sickle Cell Anemia: Baseline Data from the BABY HUG Trial

Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years.

Primary hypertension and neurocognitive and executive functioning in school-age children

Data on neurocognitive function in hypertensive children are limited. In this review, we summarize recent preliminary, early studies that suggest that children with elevated blood pressure demonstrate evidence of worse performance on direct neurocognitive testing, as well as evidence of executive dysfunction based on parent ratings, compared with matched normotensive comparison groups. Furthermore, hypertensive children may have increased prevalence of learning disabilities as well as a blunted cerebrovascular reactivity compared with normotensive controls. Larger, prospective studies are needed to confirm and further explore these emerging but preliminary findings.